system-wide assessment of wound care interventions: a ......committee members and wound care content...

Scoping Review Submitted by breaKThrough|Page1

System-wide assessment of wound care interventions: A scoping review

Prepared by:

Andrea C. Tricco, Jesmin Antony, Elise Cogo, Paul A. Kahn, Alana Harrington, Afshin Vafaei, Geetha Sanmugalingham, Charlotte Wilson, John Ivory, Laure

Perrier, Sharon E. Straus Of breaKThrough, Li Ka Shing Knowledge Institute of St. Michael’s Hospital

For:

The Wound Care Steering Committee Of the Toronto Central Local Health Integrated Network

For further info, please contact: Andrea C. Tricco Scientist, Knowledge Translation Program Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada Telephone: 416-864-6060, ext 77521, email: [email protected], fax: 416-864-5805

Submitted on January 31, 2013

Scoping Review Submitted by breaKThrough |

Table of contents

Executive Summary ............................................................................................................... 4

Introduction .......................................................................................................................... 7

Objectives ............................................................................................................................. 9

Methods ............................................................................................................................. 10

Results ................................................................................................................................ 14

Results from included systematic reviews ............................................................................ 14

Summary of effective interventions from the highest quality systematic reviews for which a meta-analysis was conducted .............................................................................................. 20

Results from included economic studies .............................................................................. 22

Summary of cost-effective interventions from the highest quality cost-effectiveness/cost-utility analyses .................................................................................................................... 27

Discussion ........................................................................................................................... 29

Acknowledgements ............................................................................................................. 37

Figure 1: Study flow ............................................................................................................. 38

Figure 2: Cost-effectiveness plane ........................................................................................ 39

Table 1: Systematic review summary characteristics ............................................................ 40

Table 2: Systematic review methodological quality .............................................................. 42

Table 3: Results for high quality systematic reviews for which a meta-analysis was not conducted (N=16) ................................................................................................................ 47

Table 4: Healing outcomes for reviews including venous and arterial leg ulcers (N=66 meta-analyses) ............................................................................................................................. 51

Table 5: Healing outcomes for reviews including pressure ulcers and sores (N=36 meta-analyses) ............................................................................................................................. 59

Table 6: Healing and hospitalization outcomes for reviews including diabetes ulcers and infections (N=25 meta-analyses) .......................................................................................... 64

Table 7: Healing outcomes for reviews including mixed acute and/or chronic wounds (N=17 meta-analyses) .................................................................................................................... 67

Table 8: Healing and hospitalization outcomes for reviews including wound infections (N=4 meta-analyses) .................................................................................................................... 69


Table 9: Healing outcomes for reviews including burns (N=4 meta-analyses) ........................ 70

Table 10: Economic study summary characteristics .............................................................. 71

Table 11: Results for costing studies (N=69) ......................................................................... 73

Table 12: Cost-effectiveness/cost-utility analyses methodological quality ............................ 81

Table 13: Cost-effectiveness/cost-utility analyses results for venous ulcers (N=14) ............... 82

Table 14: Cost-effectiveness/cost-utility analyses results for pressure ulcers (N=7) .............. 86

Table 15: Cost-effectiveness/cost-utility analyses results for surgical wounds (N=3) ............. 88

Table 16: Cost-effectiveness/cost-utility analyses results for diabetic ulcers (N=9) ............... 90

Table 17: Cost-effectiveness/cost-utility analyses results for mixed acute and/or chronic ulcers (N=2) ......................................................................................................................... 93

References .......................................................................................................................... 94

Appendix 1: Description of interventions ........................................................................... 108

Appendix 2: Scoping review approach................................................................................ 109

Appendix 3: Search strategy for the MEDLINE database ..................................................... 110

Appendix 4: Screening criteria for titles and abstracts (level 1 screening) ........................... 113

Appendix 5: Screening criteria for full-text articles (level 2 screening) ................................ 118

Appendix 6: Data abstraction form for systematic reviews ................................................. 123

Appendix 7: Data abstraction form for economic studies ................................................... 127

Appendix 8: List of included studies ................................................................................... 137


Executive Summary

What are effective interventions for wound care across the healthcare system?

• Numerous interventions are available for patients, healthcare providers, and health policy-

makers to choose from for treating patients with wounds.

• Optimal wound care management for patients with wounds is unclear.

How was the study conducted?

• Rigorous scoping review methods were used.

• Included studies were systematic reviews and economic analyses.

• All studies had to include adults who experienced a wound and report at least one of the

following outcomes: healing, admission to hospital, resources, cost or cost-effectiveness. All

interventions and comparators were included.

• The included studies were appraised to assess their methodological quality.

What did the study find?

Based on evidence from the highest quality systematic reviews for which a meta-analysis was

conducted, the following interventions are likely effective:

Wound type Effective intervention versus comparator

Venous/arterial leg ulcers

High compression stockings versus compression bandage

Elastic bandage versus inelastic bandage

Cadexomer iodine plus compression therapy versus usual care plus compression therapy

Multi-layer high compression versus single-layer compression

Pentoxifylline with or without compression versus placebo or all other treatments

2-layer stocking versus short-stretch bandage

Elastic high compression versus multi-layer inelastic compression

Tissue engineered skin versus dressings


Wound type Effective intervention versus comparator

4-layer bandage versus short-stretch bandage or versus multi-layer short-stretch bandage

Cadexomer iodine versus usual care

Pressure ulcers Hydrocolloid versus usual care

Air-fluidized beds versus usual care

Alternative foam mattress versus standard foam mattress

Electrotherapy versus sham therapy

Nutritional support versus usual care

Diabetic ulcers Artificial skin graft with usual care versus usual care alone

Hydrogel dressing versus basic wound dressing

Hydrogel versus gauze with usual care

Hyaluronic acid derivatives versus usual care

Low-frequency low-intensity noncontact ultrasound versus sharp debridement

Low-frequency high-intensity contact ultrasound versus sharp debridement

Granulocyte-colony stimulating factor versus control (unspecified)

Mixed chronic wounds

Apligraf skin graft versus usual care

Dermagraft skin graft versus usual care

Any artificial skin graft plus standard wound care versus usual care

Silver dressings versus non-silver dressings

Burns Honey versus silver sulfadizine or conventional dressings

Based on evidence from the highest quality cost-effectiveness/cost-utility analyses, the following

interventions are likely cost-effective:

Wound type Cost-effective intervention versus comparator

Venous ulcers Pentoxifylline plus usual care versus standard compression with external treatment

4-layer high compression bandages versus standard compression with external treatment

4-layer high compression bandages versus short-stretch high compression


Wound type Cost-effective intervention versus comparator bandages

Pressure ulcers Multi-disciplinary community wound care teams versus usual nursing care

Diabetic ulcers Hyperbaric oxygen therapy plus standard care versus standard care alone

Becaplermin gel containing recombinant human platelet derived growth factor plus standard care versus usual wound care alone

Diabetic foot infections

Ertapenem versus piperacillin/tazobactam

What are the next steps?

• TC LHIN’s Wound Care Steering Committee may wish to use the above findings to map

what is currently being practiced within the LHIN to ensure evidence-based and effective

practices are in place,

• TC LHIN’s Wound Care Steering Committee may wish to conduct a Delphi process with

committee members and wound care content experts to determine the area of focus for the

LHIN’s Wound Care Program,

• TC LHIN may wish to fund a network meta-analysis, which is a statistical technique that can

be used to rank all of the treatment options available, and

• The breakthrough team will prepare two manuscripts for publication based on the work of

this report.


Introduction

There are many different types of wounds, which can be broadly classified as acute and chronic

wounds [1-3]. Acute wounds can be defined as wounds that heal in “an orderly and timely

reparative process”, while chronic wounds are those that have not progressed through the ordered

process of healing to yield a functional result [3]. The main types of acute wounds include burns,

lacerations, surgical wounds, and traumatic wounds [1-3]. In contrast, the main types of chronic

wounds include wounds due to chronic disease (e.g., venous ulcers, arterial ulcers, and diabetic

ulcers), pressure ulcers, and infected surgical wounds [1-3].

Burns are the most common type of acute wound, with over two million people experiencing a

burn each year and 80,000 people hospitalized as a result of a burn per year in the United States

alone [4]. The main types of burns include superficial (or a first-degree burn), partial thickness

(or a second-degree burn), and full-thickness (or a third-degree burn) [5]. Post-surgical incisions

are another form of an acute wound, which often heal in a timely manner [6]. Deep tissue

wounds, such as complicated sternal wounds for cardiac surgery patients, can develop in 1-5% of

patients, and often result in an increased length of hospital stay [7].

It has been estimated that chronic wounds cost the healthcare system $10 billion annually in

North America alone [8]. These estimates often don’t capture indirect costs, including the

frustration, economic loss, and decreased quality of life experienced by those suffering from

chronic wounds. Surgical wounds that become infected are a form of chronic wound [9].

Individuals with chronic conditions, such as diabetes and spinal cord injuries (SCI),

immunosuppressed individuals (e.g., patients with cancer or HIV), and older adults often suffer

from impaired wound healing for a variety of reasons [3, 8]. These populations are typically at


risk for a chronic wound, as they have a decreased ability to heal appropriately and the potential

to be exposed to circumstances where chronic wounds can develop. An example is pressure ulcer

development in the SCI population.

Pressure ulcers are a significant burden to the healthcare system. It has been estimated that

pressure ulcers consume 4% of the annual National Health Service expenditure (or £1.4–£2.1

billion per year) in the United Kingdom alone [10]. In Canada, the prevalence of pressure ulcers

is between 24-26% in acute care hospitals, 28-31% in non-acute care facilities (including long-

term care and nursing homes), 21-23% in mixed settings (acute and non-acute care), and 13-17%

in community care settings [11].

Numerous interventions are available to treat acute and chronic wounds. Just as the management

of spine pain has been compared to a “supermarket” [12], the treatment of wounds can also be

described as such and decision-makers, such as patients, clinicians, and policy-makers are forced

to choose from a plethora of treatments. Furthermore, a multi-faceted approach to wound care is

often employed, so several interventions may be used concurrently. These include wound

cleansing (e.g., irrigation, providone-iodine), dressings (e.g., paraffin gauze, honey, silver-

impregnated, hydrocolloid, radiant heat dressing, semelil gel, soft silicone), skin replacement

therapy (e.g., apligraf, dermagraft, graft jacket, orcel, promogran, hyalograft, laser skin),

stockings (e.g., compression socks), Chinese herbal medicine, nutritional supplementation (e.g.,

vitamin C, collagen protein, zinc sulfate), support surfaces and off-loading devices (e.g., foam

mattress, water mattress, low air loss mattress, alternating pressure mattress), biologic agents

(e.g., protease-modulating matrix, fibroblast-derived dermal replacement, recombinant platelet-

derived growth factor), adjuvant therapies (e.g., topical negative pressure, closed-assisted

vacuum therapy, electric current, hyperbaric oxygen therapy, ultrasound, electromagnetic


therapy, laser, light, hydrotherapy), and wound care programs (e.g., case management, patient

education, multidisciplinary teams). Some of these interventions have been further elaborated

upon in Appendix 1. As the evidence of these interventions is recondite across the literature, we

were approached by the Toronto Central Local Health Integrated Network (TC LHIN) to conduct

a scoping review to identify optimal and cost-effective treatment of wounds from high quality

systematic reviews and economic analyses.

Objectives

1) To conduct a systematic search to identify effective interventions for wound care across the

healthcare system.

2) To characterize this literature regarding study characteristics (e.g., costing study/systematic

review, number of studies identified, type of study designs included, methodological quality),

patient characteristics (e.g., clinical population, mean age), wound care interventions examined,

and outcomes examined.


Methods

Our scoping review was conducted using methodologically rigorous methods proposed by

previous researchers, Arksey and O’Malley [13]. The overall approach that we use to conduct

scoping reviews at breakthrough is presented in Appendix 2. A scoping review proposal was

submitted to the TC LHIN on September 13, 2012. Feedback was received by the TC LHIN and

the proposal was revised, as necessary.

Search Strategy

Comprehensive literature searches were conducted in the following electronic databases from

inception onwards: MEDLINE (OVID interface, 1950 until October 26, 2012), EMBASE (OVID

interface, 1980 until October 26, 2012), and the Cochrane Library (Issue 10 of 12, 2012). The

search terms included both medical sub-headings (MeSH) and free text terms related to wound

care interventions. The literature searches were conducted by an experienced librarian (Laure

Perrier, Librarian for the University of Toronto, Faculty of Medicine’s Continuing Education and

Professional Development) on October 26, 2012.The full search strategy for the MEDLINE

database is presented in Appendix 3. The search strategy was limited to adults, systematic

reviews, and economic studies, using validated search filters.

The search strategy was peer reviewed by another expert librarian on our team (Elise Cogo)

using the Peer Review of Electronic Search Strategies (PRESS) checklist [14]. After this

exercise, the search strategy was amended, as necessary. The literature search results were

exported into RefWorks and then Excel to remove all duplicates from the search results across

the three databases. The results were subsequently uploaded to our SysRev Tool, proprietary

systematic review software developed by breaKThrough team members [15].


Inclusion criteria

The inclusion criteria were framed using the PICOST criteria [16], as follows:

Patients: Adults aged 18 years and older experiencing acute and chronic wounds. Acute wounds

included burns, lacerations, surgical wounds, and traumatic wounds, while chronic wounds

included those due to chronic disease (e.g., venous ulcers, arterial ulcers, and diabetic ulcers),

pressure ulcers, and infected surgical wounds.

Interventions: All wound care interventions were included. Examples include pharmacological

agents (e.g., topical agents), non-pharmacological agents (e.g., dressings, vacuum, hyperbaric

therapy), and wound care programs.

Comparators: All comparators, such as other wound care interventions; no treatment, placebo,

and usual care were eligible for inclusion.

Outcomes: Healing, cost/cost-effectiveness, admission to hospital (including readmissions), and

human resources.

Study designs: As the literature-base on wound care is extensive, we focused our review on

systematic reviews and economic studies.

Time frame: We did not limit inclusion to year of publication.

Study Selection: Screening

Prior to commencing the screening process, a calibration exercise was conducted to ensure

reliability in correctly selecting articles for inclusion. This exercise entailed screening a random

sample of 50 of the included titles and abstracts by all team members, independently. The


eligibility criteria were modified, as necessary to optimize clarity. Subsequently, two reviewers

independently screened the remainder of the search results for inclusion using a pre-defined

relevance criteria form for all levels of screening (e.g., title and abstract, full-text review of

potentially relevant articles) in our SysRev Tool. Discrepancies were resolved by discussion or

the involvement of a third reviewer. The final screening criteria can be found in Appendix 4 for

screening titles and abstracts and Appendix 5 for screening full-text articles.

Data Abstraction:

Data abstraction forms were drafted and pilot-tested by all team members independently on a

random sample of 5 articles. The data abstraction forms were revised after this exercise, as

necessary. Subsequently, two investigators independently read each article and abstracted the

relevant data. Differences in abstraction were resolved by discussion or the involvement of a

third reviewer. Separate forms were used for abstracting data from systematic reviews and

economic studies.

For systematic reviews, data items included study characteristics (e.g., number of studies

identified, type of study designs included, methodological quality, wound interventions

examined, comparators), patient characteristics (e.g., clinical population, mean age), and

outcome results. The methodological quality of systematic reviews was appraised using the

Assessment of Multiple SysTemAtic Reviews (AMSTAR tool), which gives an overall score out

of 11 [17]. A score of 8/11 was considered to be a “high quality” systematic review. Data from

all systematic reviews that conducted a meta-analysis of the outcomes of interest were

abstracted. However, the results of systematic reviews for which a meta-analysis was not

conducted were not abstracted if they were assessed as low methodological quality (AMSTAR

<8). The final data abstraction form for systematic reviews can be found in Appendix 6.


For economic studies, data items included study characteristics (e.g., type of economic

evaluation, horizon, interventions examined, comparators), patient characteristics (e.g., clinical

population, cohort used for the economic evaluation), and cost results. Further data abstraction

was conducted for cost-utility analyses (CUAs) or cost-effectiveness analyses (CEAs), as these

are considered the gold standard of economic evaluations. For example, we abstracted

incremental cost effectiveness ratios (ICERs), quality adjusted life years (QALYs), cost per

wound healed, and cost per life year from CUAs and CEAs. The methodological quality of

CUAs and CEAs was appraised using a 10-item tool developed by Drummond and colleagues

[18]. The final data abstraction form for economic studies can be found in Appendix 7.

Synthesis

The literature search results, as well as all of the abstracted data, were summarized descriptively.

An in-depth comparison of the literature-base was compiled and depicted in tables. We also

identified interventions that might be the most effective and cost-effective for patients

experiencing wounds, as well as gaps in the literature to target future research initiatives.


Results

Literature search

The flow of titles and abstracts and full-text articles is presented in Figure 1. As displayed, the

literature search resulted in 6,199 titles and abstracts, which were screened in duplicate. Of these,

421 potentially relevant full-text articles were obtained and screened in duplicate. Reasons for

exclusion of articles at the full-text level of screening included that it wasn’t a systematic review

or economic study (n=77), did not describe an intervention to treat wounds (n=35), wasn’t

written in English (n=25), did not include adults with wounds (n=22), did not examine an

outcome of interest (n=14), was a trial protocol or conference abstract (n=10) or was unable to be

located (n=6). There were 232 included studies; 110 systematic reviews (comprising 53

systematic reviews without a meta-analysis and 57 systematic reviews with a meta-analysis) plus

15 companion reports and 104 economic studies (comprising 35 CEAs/CUAs and 69 costing

studies) plus three companion reports. The references of the included studies can be found in

Appendix 8.

Results from included systematic reviews

Systematic reviews –study characteristics

The characteristics of the 110 included systematic reviews are presented in Table 1. The earliest

systematic review was published in 1997 and the most recent was published in 2012. The

majority of the reviews were published between 2006 and 2010 (46.4%). Most of the systematic

reviews were published by authors located in Europe (65.5%) and North America (20.0%). The

number of studies included in each systematic review ranged from 0 to 130, with the majority of


reviews including between two and 10 studies (50%). Most of the reviews were limited to RCTs

(68.3%).

Systematic reviews – patient characteristics

The types of patients and wounds included in the systematic reviews are presented in Table 1.

The five most prevalent types of wounds examined were described as being venous, arterial and

unspecified leg ulcers (24.6%), diabetic ulcers or infections (19.1%), mixed chronic wounds

(18.2%), pressure ulcers (15.5%), and mixed acute and chronic ulcers (10.9%). Only 31.8% of

the included systematic reviews reported on a specific patient population, which included

patients with diabetes (15.5%), chronic venous disease (8.2%), or chronic lower limb wounds

(1.8%), and patients who were elderly (2.7%), institutionalized (1.8%), ambulatory (0.91%), or

had cancer (0.91%). The five most commonly assessed wound care treatments included dressings

(29.0%), adjuvant therapies (13.6%), biologic agents (7.7%), wound cleansing (7.7%), and

topical negative pressure (7.7%). The five most common comparators were dressings (26.2%),

standard care (20.5%), placebo (18.9%), any therapy or unspecified (7.7%), and bandages

(5.6%). The duration of treatment ranged from 2 days to 18 months and the duration of follow-up

ranged from 2 days to 180 months across the included studies in the systematic reviews.

Systematic reviews – methodological quality

The methodological quality of the 110 included systematic reviews according to the AMSTAR

tool is reported in Table 2. Approximately 40% of the included reviews were rated as being high

quality, with a score of ≥8 out of a total score of 11. Consistent methodological shortcomings

across the systematic reviews included that only 35.5% used a protocol to guide their conduct,

38.2% included a list of excluded studies at level 2 screening, and 26.4% addressed or mentioned


publication bias. Conversely, methodological strengths across the systematic reviews were that

95.5% searched at least two electronic databases, 86.4% provided the characteristics of included

studies, 87.3% appraised the quality of the included studies, and 80.9% adequately used the

quality appraisal results in formulating conclusions.

Systematic reviews – outcome results

Outcome results from high quality systematic reviews that did not conduct a meta-analysis (or

non-meta-analyses) are summarized below, followed by a summary of outcomes by wound type

from systematic reviews for which a meta-analysis was conducted. From these summaries, we

then highlight the interventions most likely to be effective based on the results of only the

highest quality systematic reviews for which a meta-analysis was conducted.

Systematic reviews – outcome results for studies that did not complete a meta-analysis

The results from 16 high quality systematic reviews for which a meta-analysis was not conducted

are presented in Table 3. The majority of the systematic reviews found weak/insufficient

evidence or no difference between the interventions and comparator groups. One systematic

review suggested that revascularization with either open bypass surgery or endovascular

revascularization might improve healing of diabetic foot ulcers, yet there was insufficient

evidence to recommend one form of revascularization over another [19]. Another systematic

review found some evidence that debriding agents have a beneficial effect on healing of surgical

wounds compared to traditional gauze dressings, yet the superiority of one type of debriding

agent over another could not be established [20]. A third systematic review found that a plaster

cast might be effective for healing amputations, as well as for decreasing hospital stay compared

with elastic compression [21].


Systematic reviews – outcome results for venous and arterial leg ulcers meta-analyses

Sixty-six meta-analyses reported healing outcomes for patients with venous and arterial leg

ulcers, which are presented in Table 4. Of these, 44 meta-analyses reported on the number of

ulcers healed. Interventions that were effective for this outcome were high compression

stockings versus compression bandage [22], elastic bandage versus inelastic bandage [23], elastic

multi-layer high compression bandage versus inelastic compression [24], cadexomer iodine plus

compression therapy versus usual care plus compression therapy [25], intermittent pneumatic

compression versus compression stockings/Unna’s boot [24], multi-layer high compression

versus single-layer compression [22, 24], pentoxifylline with or without compression versus

placebo [26], 2-layer stocking versus short-stretch bandage [23], ultrasound versus no ultrasound

[27], topical negative pressure versus usual care [28], and dermagraft versus standard

compression therapy [29].

Eight meta-analyses reported healing or improvement of ulcers for patients with venous or

arterial ulcers (Table 4). Interventions that were effective for this outcome included stockings

versus bandages [30], elastic high compression versus multi-layer inelastic compression [22],

granulocyte-macrophage colony stimulating factor versus placebo [31], tissue engineered skin

versus dressings [32], and pentoxifylline versus all other treatments [26]. Four meta-analyses

reported the rate of ulcer healing (Table 4). The only intervention that was effective for this

outcome was micronized purified flavonoid versus placebo/standard care [33].

Five meta-analyses reported on the time to ulcer healing for patients with venous or arterial

ulcers (Table 4). Interventions that were effective for this outcome included bandages versus

stockings [30], micronized purified flavonoid versus placebo/standard care [33], 4-layer bandage


versus short-stretch bandage [34] or versus multi-layer short-stretch bandage [23], and topical

negative pressure versus usual care [28]. An additional five meta-analyses reported impact on the

ulcer size/area reduction (Table 4). Effective interventions included silver treatments versus non-

silver therapies [35], micronized purified flavonoid versus control (non-specified) [33],

ultrasound versus placebo/standard care [27], and cadexomer iodine versus usual care [25].

Systematic reviews – outcome results for pressure ulcers meta-analyses

Thirty-six meta-analyses reported on healing outcomes for patients with pressure ulcers and

sores, which are presented in Table 5. Of these, 25 meta-analyses focused on complete healing of

ulcers or sores. Interventions that were effective for this outcome included hydrocolloid versus

traditional dressing [36], hydrogel dressing versus hydrocolloid dressing [36], and Nimbus 3

alternating-pressure mattresses versus other alternating-pressure mattresses in the hospital setting

[36]. Seven meta-analyses reported on the healing or improvement of ulcers or sores.

Interventions that were effective for this outcome included hydrocolloid versus traditional

treatment [37], air-fluidized supports versus usual care [38], air-fluidized beds versus usual care

[39] or conventional mattresses [36], alternative foam mattress versus standard foam mattress

[39], and electrotherapy versus sham therapy [22]. One meta-analysis reported the incidence of

ulcers and found that nutritional support was more effective than usual care [40].

Systematic reviews – outcome results for diabetic ulcers meta-analyses

Twenty-five meta-analyses provided data on healing and hospitalization outcomes amongst

patients with diabetic ulcers and their results are presented in Table 6. Fifteen meta-analyses

provided data on the proportion of diabetic ulcers healed. Effective interventions for this

outcome included skin replacement therapy versus usual care [41], artificial skin graft with usual


care versus usual care alone [42], hydrogel dressing versus basic wound dressing [43], hydrogel

versus gauze with usual care [44], autologous platelet-rich plasma versus control [45], and

Chinese herbal medicine versus usual care [46].

Three meta-analyses provided data on ulcer healing or improvement for patients with diabetic

ulcers (Table 6) and the only effective intervention was Chinese herbal medicine versus usual

care [46]. Five meta-analyses provided data on non-healing ulcers and effective interventions

were Chinese herbal medicine versus usual care [46], hyaluronic acid derivatives versus usual

care [47], low-frequency low-intensity noncontact ultrasound versus sharp debridement [47], and

low-frequency high-intensity contact ultrasound versus sharp debridement [47]. One meta-

analysis provided data on the number of hospital days and granulocyte-colony stimulating factor

was more effective than control (unspecified) [48].

Systematic reviews – outcome results for mixed acute and/or chronic wounds meta-analyses

Seventeen meta-analyses reported healing outcomes among patients with mixed acute and/or

chronic wounds and their results are presented in Table 7. None of the interventions were

effective for patients with acute or mixed acute/chronic wounds. Effective interventions to heal

chronic wounds included hydrocolloid dressing versus conventional dressing [49], apligraf skin

graft versus usual care [42], dermagraft skin graft versus usual care [42], and any artificial skin

graft plus standard wound care versus usual care [42]. An effective intervention to reduce ulcer

size was silver dressing versus non-silver dressing [50]. Conflicting results were found for

autologous platelet-rich plasma versus usual care with or without placebo [51].

Systematic reviews – outcome results for wound infections meta-analyses


Four meta-analyses reported on treating infection, wound resolution, and length of

hospitalization for patients with wound infections and the results are presented in Table 8.

Fluoroquinolone treatment (including ciprofloxacin) was more effective than beta-lactam

antibiotics in treating infection [52]. Topical negative pressure/vacuum associated closure was

more effective than conventional therapy for wound resolution [53]. Finally, vacuum-assisted

closure was more effective than conventional therapy [54]. None of these systematic reviews

were of high methodological quality.

Systematic reviews – outcome results for burns meta-analyses

Four meta-analyses reported healing outcomes for burns and their results are presented in Table

9. Honey was more effective than silver sulfadizine and conventional dressings in a high quality

systematic review that assessed impact on the time to healing of the wound[2].

Summary of effective interventions from the highest quality systematic reviews for which a meta-analysis was conducted

Based on the highest quality systematic reviews for which a meta-analysis was conducted, the

following interventions are likely effective:

• Patients with venous or arterial leg ulcers - high compression stockings versus compression

bandage [22], elastic bandage versus inelastic bandage [23], cadexomer iodine plus

compression therapy versus usual care plus compression therapy [25], multi-layer high

compression versus single-layer compression [22], pentoxifylline with or without

compression versus placebo or all other treatments [26], 2-layer stocking versus short-stretch

bandage [23], elastic high compression versus multi-layer inelastic compression [22], tissue


engineered skin versus dressings [32], 4-layer bandage versus short-stretch bandage [23] or

versus multi-layer short-stretch bandage [23], and cadexomer iodine versus usual care [25].

• Patients with pressure ulcers - hydrocolloid versus traditional treatment [37], air-fluidized

beds versus usual care [39], alternative foam mattress versus standard foam mattress [39],

electrotherapy versus sham therapy [22], and nutritional support versus usual care [40].

• Patients with diabetic ulcers - artificial skin graft with usual care versus usual care alone [42],

hydrogel dressing versus basic wound dressing [43], hydrogel versus gauze with usual care

[44], hyaluronic acid derivatives versus usual care [47], low-frequency low-intensity

noncontact ultrasound versus sharp debridement [47], low-frequency high-intensity contact

ultrasound versus sharp debridement [47], and granulocyte-colony stimulating factor versus

control (unspecified) [48].

• Patients with mixed chronic wounds - apligraf skin graft versus usual care [42], dermagraft

skin graft versus usual care [42], any artificial skin graft plus standard wound care versus

usual care [42], and silver dressings versus non-silver dressings [50].

• Patients with burns - honey versus silver sulfadizine or conventional dressings [2].


Results from included economic studies

Economic studies – study characteristics

The characteristics of the 104 included economic studies are presented in Table 10. The earliest

economic study was published in 1982 and the most recent was published in 2012. The majority

of the economic studies were published between 2006 and 2010 (31.7%). Most of the economic

studies were published by authors located in Europe (43.3%) and North America (41.3%). The

majority of the studies were costing studies (66.3%), while 11.5% were CUAs/CEAs combined

and 22.1% were CEAs alone. Most of the economic studies included a total sample size of 10 to

100 patients.

Economic studies – patient characteristics

Most of the patient populations in the economic studies were elderly (59.6%), followed by

patients with chronic venous disease (27.9%) or diabetes (21.2%), and surgical/trauma patients

(11.5%; Table 10). The setting ranged from inpatients (including acute and long-term care)

(36.6%) to home care (18.3%). The types of wounds examined in these studies included venous

ulcers (27.9%), diabetic ulcers or infections (21.2%), pressure ulcers (22.1%), surgical wounds

or infections (11.5%), mixed wounds (16.3%), and other wound infections (1.0%). The five most

common treatments given to these patients for their wound care included dressings (59.6%),

programs/guidelines or systems changes (23.1%), mattresses or pressure off-loading devices

(7.7%), surgery (7.7%), oral or intravenous antibiotic treatment (7.7%), and hyperbaric oxygen

therapy or use of another device (7.7%). The five most common comparators were dressings

(36.5%), standard care (26.9%), programs/guidelines or systems changes (6.7%), mattresses or


pressure off-loading devices (5.8%), topical negative pressure (4.8%), and oral or intravenous

antibiotic treatment (4.8%).

Economic studies – outcome results

Outcome results from economic studies regarding resource utilization are summarized below.

This section is followed by the methodological quality of the included CEAs/CUAs and their

respective outcome results by wound type. Using these summaries, we then highlight the

interventions most likely to be cost-effective based on the results of the highest quality

CEAs/CUAs.

Economic studies – resource outcome results

Sixty-nine costing studies reported data on resource outcomes, which are presented in Table 11.

Numerous interventions and comparators were examined for different types of wounds and a

wide variation was observed in the resources required for these interventions. For dressings,

personnel time was usually the major cost factor, based on the frequency and number of dressing

changes required by nurses. For diabetic patients with severe ulcers, hospitalization was usually

the major cost factor due to foot infections and amputations. The mean total cost per patient

ranged from $15.6 United States dollars (US) for hydrocolloid dressing [55] to $445,678

Swedish Kronan (SEK) for reamputation (i.e., for patients requiring a second amputation on

another limb) [56]. The mean intervention cost per patient ranged from $0.52 Australian dollars

(AU) for dry absorbent dressings [57] to $20,845 Spanish pesetas (Pts) for collagenase ointment

treatment [58]. Average personnel costs per patient ranged from US$2.26 for hydrocolloid

dressings [55] to $57,277.9 Yen (¥) for a hospital incentive system with wound, ostomy, and

continence nurses [59]. Finally, average hospital costs per patient ranged from $83 Haitian


Gourdes (HTG) for homemade wound vacuum-dressing system [60] to US$14,410.0 for

conventional hospital beds [61].

CEAs/CUAs – methodological quality

The methodological quality of the 35 included CEAs/CUAs according to the Drummond tool

[18] is presented in Table 12. Approximately 89% of the CEAs/CUAs had a score of 7 or higher

out of a total possible score of 10 indicating they are high quality. The one consistent

methodological shortcoming across the CEAs/CUAs was that only 34.3% established the

effectiveness of the wound care intervention using data from systematic reviews, RCTs or other

types of studies (e.g., observational studies) that had sufficiently large sample sizes. Since

effectiveness needs to be established prior to conducting a CEA/CUA, this was considered a

major limitation of the majority of the CEAs/CUAs. As such, the 12 analyses that met this

criterion were considered higher methodological quality compared with the other analyses.

Consistent methodological strengths across the CEAs/CUAs were that all clearly described the

question, measured costs and consequences in appropriate physical units, and credibly valued

costs and consequences.

CEAs/CUAs – economic results for venous ulcers

The results from 14 of the included CEAs/CUAs examining treatments for venous ulcers are

presented in Table 13. Based on these results, cost-effective interventions that were found to be

both more effective and less costly were micronized purified flavonoid fraction plus standard

therapy versus standard compression with external treatment [62], pentoxifylline plus usual care

versus standard compression with external treatment [63], four-layer high compression bandages

versus standard compression with external treatment [64] or versus short-stretch high


compression bandages [63]. Additional cost-effective interventions which were considered less

costly with similar effectiveness included pinch grafting surgery in primary care versus pinch

grafting surgery in the hospital [65] and hydrocolloid dressing versus Vaseline gauze [66].

Furthermore, skin protectant no-sting barrier film plus compression with dressings was more

effective and had similar costs compared to standard compression with external treatments [67].

For the three CEAs in which interventions were found to be both more effective yet more costly

(one of which was a high quality CEA [68]), incremental cost-effectiveness ratios are presented

in Table 13 [68-70]. Four CEAs/CUAs found the other interventions were either more costly

with similar effectiveness versus comparators, less effective versus comparators, had a similar

cost and effectiveness versus comparators, or the costing analysis was inconclusive.

CEAs/CUAs – economic results for pressure ulcers

The results from 7 of the included CEAs/CUAs examining treatments for pressure ulcers are

presented in Table 14. Based on these results, cost-effective interventions which were found to

be both more effective and less costly were hydrocolloid wafer dressing versus saline gauze [71],

advanced dressings versus conventional simple and saline dressings [72], collagenase-containing

ointment plus paraffin gauze and absorbent bandages after saline versus hydrocolloid alone [73],

and multi-disciplinary community wound care teams versus usual nursing care [74]. An

additional cost-effective intervention was self-adhesive polyurethane foam dressing, which had a

similar effectiveness and was less costly compared to moist gauze dressing with saline [75]. One

CEA found the intervention to be both more effective yet more costly, and the incremental cost-

effectiveness ratio is presented in Table 14 [76]. Finally, type 1 collagen had a similar

effectiveness, yet was more costly compared with hydrocolloid [77].


CEAs/CUAs – economic results for surgical wounds

Three CEAs examined treatments for surgical wounds and their results are presented in Table 15.

Negative-pressure wound therapy was cost-effective compared to moist wound therapy since it

was found to be both more effective and less costly in one CEA [78]. Another CEA found that

oral linezolid during hospitalization and after discharge was more cost-effective than IV

vancomycin during hospitalization followed by oral linezolid after discharge or compared to IV

vancomycin during hospitalization and after discharge [79]. The third CEA, which was the only

one that met the effectiveness methodological criterion, found that occlusive moist-environment

nongauze-based materials had a similar effectiveness yet were more costly compared with gauze

dressings [80].

CEAs/CUAs – economic results for diabetic ulcers

Seven CEAs/CUAs examined treatments for diabetic ulcers and their results are presented in

Table 16. Three of these examined interventions were found to be cost-effective based on being

both more effective and less costly. Hyperbaric oxygen therapy plus standard care was cost-

effective compared to standard care alone in a high quality CUA/CEA [81], this same result was

also found in another CUA/CEA which followed patients one year or more after the intervention

[82]. Both intensified treatment in a specialized outpatient hospital department [83] and

Becaplermin gel containing recombinant human platelet derived growth factor plus standard care

were cost-effective compared with usual care [83] or good wound care alone [84]. Additional

cost-effective interventions were cadexomer iodine ointment, which was less costly but had a

similar effectiveness to standard dressings [85] and the Optima Diab walker compared to the


total contact casting standard off-loading device [86]. The final CUA/CEA found that all

interventions had similar effectiveness and different costs [87].

Two CEAs/CUAs examined diabetic foot infections and their results are presented in Table 16.

Both of these examined interventions that were found to be cost-effective based on being both

more effective and less costly. Ertapenem was cost-effective compared to

piperacillin/tazobactam in a high quality CEA/CUA [88]. Furthermore, filgrastim plus antibiotics

(i.e., a combination of ceftazidime, amoxicillin, flucloxacillin and metronidazole) was cost-

effective versus placebo plus antibiotics (identical combination above) in a CEA that did not

establish effectiveness prior to conducting the economic analysis [89].

Two CEAs/CUAs examined mixed wound types and their results are presented in Table 17. Both

of these examined interventions that were found to be cost-effective based on being both more

effective and less costly. Bio-electric stimulation therapy was cost-effective compared to

standard care for chronic non-healing wounds [90]. For chronic wounds, a specialty

enterostomal/advanced wound and ostomy skills nursing agency seeing patients exclusively was

cost-effective versus a hybrid nursing care model [91]. Neither of these CEAs/CUAs adequately

established the effectiveness of the intervention for the economic analysis so were not considered

high quality.

Summary of cost-effective interventions from the highest quality cost-effectiveness/cost-utility analyses

Based on the highest quality evidence, the following interventions are likely cost-effective:


• Patients with venous ulcers - pentoxifylline plus usual care versus standard compression with

external treatment [92], and four-layer high compression bandages versus standard

compression with external treatment [64] or versus short-stretch high compression bandages

[63].

• Pressure ulcers - multi-disciplinary community wound care teams versus usual nursing care

[74].

• Diabetic ulcers - hyperbaric oxygen therapy plus standard care versus standard care alone

[81] and Becaplermin gel containing recombinant human platelet derived growth factor plus

standard care versus usual wound care alone [84].

• Diabetic foot infections - Ertapenem versus piperacillin/tazobactam [88].


Discussion

We conducted a comprehensive scoping review to identify optimal and cost-effective wound

care interventions. Data from 110 systematic reviews and 104 economic studies were scrutinized

and wound care interventions that are likely optimal and cost-effective were identified. These

reviews and economic studies examined numerous treatments and comparators and used

different outcomes to assess effectiveness and costs. Frequently, the interventions considered in

one review or cost-effectiveness analysis comprised the comparator group in another review or

cost-effectiveness analysis. This renders the interpretation of our findings difficult and our

results cannot be used to rank the effectiveness and respective cost-effectiveness of these

interventions.

We included data from 110 systematic reviews, the first of which was published in 1997. This

indicates a huge explosion in the number of systematic reviews in this area, with the majority

conducted between 2006 and 2010. Based on this, wound care is an area of high priority and it is

clear that researchers and clinicians are interested in finding optimal ways to improve quality of

care for patients with wounds.

Although numerous reviews and economic studies were included examining a broad range of

outcomes, research gaps were apparent. For systematic reviews, the majority of the evidence

focused on chronic wounds, including leg ulcers (3 high-quality systematic reviews without a

meta-analysis plus 66 meta-analyses), pressure ulcers (4 high-quality systematic reviews without

a meta-analysis plus 36 meta-analyses), diabetic foot ulcers (3 high-quality systematic reviews

without a meta-analysis plus 25 meta-analyses), and infected wounds (1 high-quality systematic

review without a meta-analysis plus 4 meta-analyses). Acute wounds were examined less


frequent and included surgical wounds (3 high-quality systematic reviews without a meta-

analysis) and burns (1 high-quality systematic review without a meta-analysis plus 4 meta-

analyses). No systematic reviews were identified on other types of acute wounds, such as

lacerations or trauma. Only systematic reviews focused on diabetic foot ulcers, surgical wounds,

and infected wounds reported on hospitalization outcomes; the rest of the reviews focused on

healing outcomes.

Our scoping review identified a large research gap in cost-effectiveness evaluations of wound

care interventions. Compared to the large economic burden of wound care in Canada and

internationally [8, 10], and the multitude of wound care interventions available, relatively few

high quality cost-effectiveness analyses were identified. The 12 high quality CEAs/CUAs that

were identified assessed the following types of wounds: venous ulcers (n=7 studies), diabetic

ulcers (n=2), pressure ulcers (n=1), surgical wounds (n=1), and diabetic foot infections (n=1).

High quality CEAs/CUAs were not identified on burns, lacerations or trauma.

After including data from 110 systematic reviews, we found that some interventions are likely to

be more effective than others. For patients with venous or arterial leg ulcers, high compression

stockings versus compression bandage [22], elastic bandage versus inelastic bandage [25],

cadexomer iodine plus compression therapy versus usual care plus compression therapy [25],

multi-layer high compression versus single-layer compression [22], pentoxifylline with or

without compression versus placebo or all other treatments [26], 2-layer stocking versus short-

stretch bandage [25], elastic high compression versus multi-layer inelastic compression [22],

tissue engineered skin versus dressings [32], 4-layer bandage versus short-stretch bandage [25]or

versus multi-layer short-stretch bandage [25], and cadexomer iodine versus usual care [25] were

found to be effective. For patients with pressure ulcers, hydrocolloid versus traditional treatment


[37], air-fluidized beds versus usual care [39], alternative foam mattress versus standard foam

mattress [39], electrotherapy versus sham therapy [22], and nutritional support was more

effective versus usual care [40]. For patients with diabetic ulcers, artificial skin graft with usual

care versus usual care alone [42], hydrogel dressing versus basic wound dressing [43], hydrogel

versus gauze with usual care [44], hyaluronic acid derivatives versus usual care [47], low-

frequency low-intensity noncontact ultrasound versus sharp debridement [47], low-frequency

high-intensity contact ultrasound versus sharp debridement [47], and granulocyte-colony

stimulating factor versus control (unspecified) [48] were effective. For patients with mixed

chronic wounds, apligraf skin graft versus usual care [42], dermagraft skin graft versus usual

care [42], any artificial skin graft plus standard wound care versus usual care [42], and silver

dressings versus non-silver dressings [50] were effective. Finally, for patients with burns, honey

was effective versus silver sulfadizine or conventional dressings [2].

Cost-effectiveness studies can have eight possible overall results, which are often represented

graphically as quadrants on a cost-effectiveness plane [93], as depicted in Figure 2. The

possibilities for the intervention versus comparator are as follows: 1) more effective and less

costly; 2) more effective and similar costs; 3) similar effectiveness and less costly; 4) more

effective and more costly; 5) similar effectiveness and more costly; 6) less effective and less

costly; 7) less effective and similar costs; and 8) less effective and more costly. Results from

possibilities 1-3 are considered to be cost-effective; whereas possibility 5 is not cost-effective

and possibilities 6-8 are less effective. Situation 4 requires judgment by the decision-maker to

interpret whether it is cost-effective [94]. In such cases, a study should report an incremental

cost-effectiveness ratio (ICER) that has calculated the relative difference in costs to the

difference in effectiveness between the intervention and comparator using this calculation: (Cost


of the intervention – Cost of the comparator) ÷ (Effectiveness of the intervention – Effectiveness

of the comparator). Smaller values indicate better cost-effectiveness [18].

Out of 35 cost-effectiveness studies (CEAs/CUAs) reviewed, 12 were deemed to be of higher

methodological quality based on having established effectiveness. Of these 12, seven reported

cost-effective results for the intervention studied. For patients with venous ulcers, pentoxifylline

plus usual care versus standard compression with external treatment [92], and four-layer high

compression bandages versus standard compression with external treatment [64] or versus short-

stretch high compression bandages [63] were found to be cost-effective (and these cost-effective

interventions were also found to be effective in the higher quality meta-analyses discussed

above). For patients with pressure ulcers, multi-disciplinary community wound care teams

comprising of trained community pharmacists and nurses in the nursing home versus usual

nursing care in the nursing home [74] were found to be cost-effective. For patients with diabetic

ulcers, hyperbaric oxygen therapy plus standard care versus standard care alone [81], and

Becaplermin gel containing recombinant human platelet derived growth factor plus standard care

versus good wound care alone [84] were found to be cost-effective. Finally, for patients with

diabetic foot infections, Ertapenem versus piperacillin/tazobactam [88] was cost-effective.

One of the 12 high quality CEAs/CUAs examined community based leg ulcer clinics with

trained nurses using a unique graduated four layer compression bandaging system versus

patients' usual home care. The authors found that the intervention was more effective yet more

costly than usual care with an incremental cost-effectiveness ratio result of £2.46 per ulcer-free

week gained (i.e. it costs an extra £2.46 for each additional week without an ulcer) [68]. Four of

the 12 high quality CEAs/CUAs did not find the interventions were cost-effective [80, 95-97].


Our results suggest the need for a network meta-analysis, given the numerous interventions and

comparators available. Network meta-analysis is a statistical technique that can be used to select

the best treatment option available. In a situation where we may have direct comparisons of

treatments (e.g. T1 versus T3 and T2 versus T3); indirect methods attempt to use the common

comparator link T3 to yield an indirect comparison of T1 versus T2. There are various reasons

that lead to a lack of availability of a direct comparison, such as the lack of comparison between

interventions based on usual treatment or the scarcity of resources to conduct RCTs for every

single intervention comparison. In these situations, performing an indirect treatment comparison

is beneficial. Based on our preliminary findings, a suitable topic for network meta-analysis is to

examine stockings versus bandages for patients with venous or arterial leg ulcers. This will be a

more focused review and the results will likely be of interest to decision-makers, including those

at the TC LHIN.

Few of the included systematic reviews were rated as being of high methodological quality

according to the AMSTAR tool [17]. Consistent methodological shortcomings include not using

a protocol to guide their conduct, not including a list of excluded studies at level 2 screening, and

not addressing or at least mentioning publication bias. Furthermore, some studies only gave

wound care patients 2 days of treatment or followed patients for 2 days. The utility of these short

studies is questionable and studies of longer duration are recommended.

The major methodological quality limitation found in the CEAs/CUAs reviewed was that the

majority did not adequately establish the effectiveness of the wound care intervention using data

from systematic reviews, RCTs or other types of studies (e.g., observational studies) that had

sufficiently large sample sizes. Many of the cost-effectiveness studies did not include

information on patient-reported quality of life outcomes or adverse events. Furthermore, many of


the CEAs/CUAs did not assess long-term cost-effectiveness. The choice of timeframe for an

economic evaluation might significantly affect the cost-effectiveness results. Given the chronic

nature of many types of wounds, economic modeling of a longer time horizon would provide a

clearer picture in many circumstances. For example, an intervention might be more effective yet

more costly in the first two months but this might result in better cost-effectiveness due to overall

fewer additional interventions required in the future.

Given the large scope of our scoping review and short timeline for its completion, it is difficult

for us to make any recommendations on important elements for the TC LHIN to consider

regarding the Canadian context. Eight of the systematic reviews were from authors with a

Canadian affiliation [36, 42, 98-103], yet we do not know if the studies included in these reviews

were conducted in Canada. Of note, only one of these systematic reviews was rated as being high

quality [42]. However, all of the interventions found to be effective from data from systematic

reviews are likely transferrable to the Canadian context. For example, the effective bandages,

stockings, dressings, and skin grafts, are widely available and likely of relevance to the TC

LHIN. Furthermore, the results from a low quality systematic review without a meta-analysis

might be of interest to the TC LHIN. This systematic review was conducted by the Medical

Advisory Secretariat of the Ontario Ministry of Health and Long-term Care and they found that

multidisciplinary wound care teams effectively healed wounds for patients with chronic wounds

compared to patients managed without a wound care team [99].

Specific to the Canadian context for the CEAs/CUAs, only one of the 12 high quality cost-

effectiveness analyses was conducted in Canada [81]. Half of the 12 high quality CEAs/CUAs

were conducted in the UK, while three were from the rest of Europe (i.e. Sweden, The

Netherlands and Ireland) and two from Australia and New Zealand. In considering the possible


applicability of these 11 other cost-effectiveness studies to the Canadian context, several factors

need to be assessed, including the perspective (e.g., healthcare system, society, provider, etc.) of

the economic evaluation (which are provided in the Tables below), the type of healthcare system

(e.g., publicly-funded healthcare), the local practice of medicine, the local costs, and the

sensitivity analyses. The results of the sensitivity analyses indicate the changes to parameters that

could significantly change the study’s overall findings, thereby providing an estimate of the

uncertainty of the results. Of the 11 non-Canadian high quality CEAs/CUAs, one found that

healing rates may affect the overall findings(with the intervention no longer being cost saving if

the improvement in monthly healing rates decreases to 24%) [84]. Three studies did not report

sensitivity analyses [80, 95, 104] and the other seven reported that none were significant. A

comparison of local costs (e.g., for the intervention materials used, personnel time,

hospitalization) to the Canadian context needs to be assessed on a case-by-case basis for each

study. In addition, some of the studies did not report a detailed breakdown of the costs involved,

rendering comparisons to the Canadian context more difficult.

There are some limitations to our scoping review. Although we appraised the methodological

quality of the included studies (which is a step that is usually skipped in scoping reviews [13]),

we are unable to comment on the quality of the included studies in the systematic reviews and

cost-effectiveness analyses. Due to the three month timeline for conduct of this rapid scoping

review, we were unable to fully scan the reference lists of included reviews and economic

analyses and we were unable to contact study authors for further information. We identified 25

studies that were written in languages other than English and these will need to be assessed for

inclusion in the future. We also need to continue searching for grey literature and contacting

authors of systematic review protocols and conference abstracts. These activities will be


conducted for the systematic review publications that result from this report, including an

overview of the 110 systematic reviews and a systematic review of the 35 CEAs/CUAs.


Acknowledgements

We thank the TC LHIN for their generous funding. We also thank Wai-Hin Chan, the business

manager of breakthrough, for her support throughout the project and David Newton, the web

developer of breakthrough, for managing the project in the SysRev Tool. Finally, we thank

Jennifer D’Souza for formatting the references for this report and Judy Tran for obtaining the

potentially relevant full-text articles.


Figure 1: Study flow


Figure 2: Cost-effectiveness plane


Table 1: Systematic review summary characteristics

Characteristic # of systematic reviews (N=110 total)

% of systematic reviews

Year 1997-2000 2001-2005 2006-2010

2011 - present

8 7.27

23 20.91 51 46.36 28 25.45

Country of conduct Europe (39 of these are from the UK)

North America Asia

Australia South America

Not reported

72 65.45 22 20.00 7 6.36 6 5.45 2 1.82 1 0.91

Number of studies included 0-1

2 - 10 11 - 20

21-30 31-40

41-100 >100

5 4.55

55 50.00 22 20.00 11 10.00 6 5.45 8 7.27 3 2.73

Study designs included* RCT OBS

NRCT CBA/ITS

99 68.28 27 18.62 18 12.41 1 0.69

Patient population Not reported/specified

Diabetes Chronic venous disease

Elderly Chronic lower limb wounds

Inpatients/institutionalized Ambulatory patients

Cancer

75 68.18 17 15.45 9 8.18 3 2.72 2 1.82 2 1.82 1 0.91 1 0.91

Type of wound Leg ulcers

Diabetic ulcer/infection Mixed chronic wounds

Pressure ulcers/sores Mixed acute and chronic wounds

Surgical wounds/infection Wound infection

Mixed acute wounds Not reported

27 24.55 21 19.09 20 18.18 17 15.45 12 10.91 5 4.55 5 4.55 2 1.82 1 0.91

Interventions examined* Dressings

Adjuvant therapies

45 29.03 21 13.55


Characteristic # of systematic reviews (N=110 total)

% of systematic reviews

Biologic agents Wound cleansing

Topical negative pressure Support surfaces

Skin replacement therapy Bandages

Nutritional supplementation Stockings

Surgical Oral treatment

Wound care programs Chinese herbal medicine

14 9.03 12 7.74 12 7.74 12 7.74 9 5.81 8 5.16 6 3.87 5 3.23 5 3.23 3 1.94 2 1.29 1 0.65

Comparators examined* Dressings

Standard care Placebo

Any therapy/Unspecified Bandages

Wound cleansing Support surfaces

Oral treatment Nutritional supplementation

Surgical Adjuvant therapies

Stockings Skin replacement therapy

Wound care programs Biologic agents

51 26.15 40 20.51 37 18.97 15 7.69 11 5.64 9 4.62 7 3.59 5 2.56 4 2.05 4 2.05 4 2.05 3 1.54 2 1.03 2 1.03 1 0.51

Note: * Numbers do not add up to 110, as the systematic reviews contributed data to more than one category. Abbreviations: CBA controlled before-after, ITS interrupted time-series, NRCT non-randomized clinical trial, OBS observational study, RCT randomized clinical trial, UK United Kingdom.


Table 2: Systematic review methodological quality

SYSTEMATIC REVIEW

An ‘a priori’

designed provided

Duplicate study

selection

Comprehensive literature

search performed

Status of publication used as an inclusion criterion

A list of included

and excluded studies

provided

Characteristics of included

studies provided

Scientific quality of included studies

assessed and

documented

Scientific quality of

the included studies used appropriately

in formulating conclusions

Methods used to

combine findings of studies is

appropriate

Likelihood of

publication bias is

assessed

Conflict of

interest is stated

AMSTAR RATING*

Adderley 2007 Y N Y Y Y Y Y Y Y N Y 9

Sari 2006 Y N Y Y UC Y Y Y Y N Y 8

Amsler 2009 UC UC Y N N Y N NA N N Y 3

Aziz 2011 Y Y Y Y UC Y Y Y Y N Y 9

Barber 2008 UC Y Y UC N Y Y Y Y N Y 7

Bardy 2008 N Y Y N N Y Y Y N Y N 6

Bergin 2006 Y UC Y Y NA NA Y NA Y NA Y 6

Berliner 2003 UC N Y UC N Y N NA N N Y 3

Blozik 2008 UC UC Y UC N N Y N N N N 2

van den Boogaard 2008

UC N Y Y N Y Y Y N N N 5

Bouza 2005 N Y Y Y N Y Y Y Y N Y 8

Bouza2005 UC UC Y N N Y Y Y N Y Y 6

Bradley 1999 UC N Y Y Y Y Y Y Y Y Y 9

Bradley 1999 UC N Y Y Y Y Y Y Y Y Y 9

Carter 2010 UC N Y N N Y Y Y Y Y Y 7

Chambers 2007 UC Y Y Y N Y Y Y Y N N 7

Chen 2010 UC UC Y UC N Y Y Y Y N Y 6

Coleridge-Smith 2005

UC UC Y Y N Y Y Y N N Y 6

Cruciani 2005 UC UC Y Y N Y Y Y Y Y N 7


SYSTEMATIC REVIEW

An ‘a priori’

designed provided

Duplicate study

selection


search performed


A list of included


provided


studies provided


assessed and

documented




Methods used to


appropriate

Likelihood of

publication bias is

assessed

Conflict of

interest is stated

AMSTAR RATING*

Cruciani 2011 Y Y Y Y Y Y Y Y Y Y Y 11

Cullum 2004 Y Y Y Y Y Y Y Y Y N Y 10

Cullum 2001 UC Y Y Y Y Y Y Y Y UC Y 9

Cullum 2008 UC UC Y N N N Y Y N NA Y 4

Cullum 2011 Y Y Y Y Y Y Y Y Y N Y 10

Damini 2010 UC Y Y N N Y Y N Y N Y 6

Dat 2012 Y Y Y UC Y Y Y Y Y N Y 9

Dumville 2011 Y Y Y Y Y Y Y Y Y Y Y 11




E.C.R.I. 2001 UC UC Y Y N Y Y Y N UC N 5

Edwards 2012 Y UC Y Y Y Y Y Y Y N Y 9

Evans 2001 N Y N Y N N Y Y N N N 4

Falagas 2006 UC Y Y N N Y Y Y Y Y N 7

Fernandez 2012 Y Y Y UC Y Y Y Y Y NA N 8

Fitzgerald 2010 UC N Y UC N Y Y N N N Y 4

Flemming 2008 Y Y Y Y Y Y Y UC Y N Y 9

Fletcher 1997 UC Y Y Y N N N Y Y N Y 6

MAS Ontario 2009 UC UC Y N N Y Y Y Y N Y 6

MAS Ontario 2005 UC UC Y Y N Y Y Y UC N Y 6

MAS Ontario 2009 UC N Y Y N Y Y Y Y N Y 7

Heyneman 2007 UC N Y N N Y Y Y Y N N 5


SYSTEMATIC REVIEW

An ‘a priori’

designed provided

Duplicate study

selection


search performed


A list of included


provided


studies provided


assessed and

documented




Methods used to


appropriate

Likelihood of

publication bias is

assessed

Conflict of

interest is stated

AMSTAR RATING*

Hinchliffe 2012 UC Y Y N N Y Y Y Y Y Y 8

Hinchliffe 2008 UC Y Y N N Y Y Y Y N Y 7

Ho 2005 Y Y Y Y N Y Y Y Y N Y 9

Hu 2010 N Y Y N N Y Y Y Y N Y 7

Hunt 2011 N N Y N N Y Y Y N N Y 5

Johannsen 1998 N Y Y N Y Y N N N N N 4

Jones 2007 Y Y Y Y Y Y Y Y Y N Y 10

Jull 2009 Y Y Y Y Y Y Y Y Y Y Y 11

Jull 2011 Y Y Y UC Y Y Y Y Y Y Y 10

Kranke 2012 Y Y Y UC Y Y Y Y Y N Y 9

Langer 2008 Y Y Y Y Y Y Y Y Y N Y 10

Lewis 2001 UC Y Y Y Y N Y Y Y Y Y 9

Lima 2010 N Y Y N N Y N N N N Y 4

Lo 2009 N UC Y Y Y Y Y Y Y Y N 8

Lo 2008 N UC Y Y N Y Y Y Y N N 6

Lucas 2000 N Y Y Y N Y Y Y Y N N 7

Margolis 1999 N N Y Y N Y UC N N N N 3

Martinez-Zapata 2012 Y Y Y N Y Y Y Y Y N Y 9

Martinez-Zapata 2008 UC Y Y N Y Y Y Y Y N N 7

Mason 1999 UC UC UC UC N Y N NA N N N 1

McGaughey 2009 UC Y Y N N Y Y Y Y N N 6

McGinnis 2011 Y Y Y Y Y Y Y Y Y Y Y 11

McInnes 2011 Y Y Y Y Y Y Y Y Y Y Y 11


SYSTEMATIC REVIEW

An ‘a priori’

designed provided

Duplicate study

selection


search performed


A list of included


provided


studies provided


assessed and

documented




Methods used to


appropriate

Likelihood of

publication bias is

assessed

Conflict of

interest is stated

AMSTAR RATING*

Moore 2012 Y Y Y Y NA NA NA NA NA NA Y 5

Moore 2001 N Y Y N N N Y Y N NA N 4

Moore 2008 Y Y Y Y N N Y Y UC N N 6

Moore 2010 Y Y Y UC NA NA NA NA Y NA Y 5

Mwipatayi 2004 N N Y N N N Y Y N NA N 3

Nawijn 2005 N Y Y N N Y Y Y N N N 5

Nelson 2011 UC N Y N N Y Y UC N NA Y 4

Nelson 2009 Y Y Y Y Y Y Y UC Y N Y 9

Nelson 2006 UC Y Y Y Y Y Y Y Y Y Y 10

Nelson 2011 Y Y Y N Y Y Y N Y N Y 8

Nble-Bell 2008 N Y Y UC Y Y Y Y Y N N 7

O’Donnell 2006 UC UC Y N N N Y Y Y N N 4

O'Meara 2001 UC Y Y Y N Y Y Y Y N N 7

O'Meara 2010 Y Y Y Y Y Y Y Y Y Y Y 11

O'Meara 2009 Y Y Y Y N Y Y Y N N Y 8

O'Meara 2009 Y Y Y Y Y Y Y Y Y Y Y 11

Palfreyman 1998 UC Y Y N N Y Y Y Y N N 6

Palfreyman 2007 UC Y Y Y Y Y Y Y Y Y Y 10

Pan 2010 UC UC Y N N Y Y Y UC N Y 5

Peters 2012 UC UC Y N N Y Y Y Y N Y 6

Pham 2003 UC UC Y Y N Y Y Y N N Y 6

Ramundo 2009 UC UC Y N N Y N NA N N UC 2

Reddy 2010 UC UC Y UC N Y Y Y Y N Y 6


SYSTEMATIC REVIEW

An ‘a priori’

designed provided

Duplicate study

selection


search performed


A list of included


provided


studies provided


assessed and

documented




Methods used to


appropriate

Likelihood of

publication bias is

assessed

Conflict of

interest is stated

AMSTAR RATING*

Reddy 2008 UC UC Y N N Y Y Y N N Y 5

Roeckl-Wiedmann 2005 Y UC Y Y N N Y Y Y Y N 7

Roukis 2009 UC UC Y Y N Y UC Y N N Y 5

Sadat 2008 UC UC Y UC N Y N NA N N N 2

Schuren 2005 UC UC Y Y N Y Y Y Y N Y 7

Singh 2004 UC UC N Y N Y Y Y N N N 4

Smith 2011 Y Y Y Y Y Y Y Y N UC Y 9

Storm-Versloot 2010 Y Y Y Y Y Y Y Y Y UC Y 10

Stratton 2005 UC UC Y UC Y Y Y Y Y Y Y 8

Suissa 2011 UC UC Y UC N Y N NA N N Y 3

TenBrook 2004 UC UC N UC N Y N NA N Y Y 3

Ubbink 2008 Y Y Y Y Y Y Y Y Y UC Y 10

Ubbink 2008 UC Y Y Y N Y Y Y Y N N 7

Vermeulen 2012 Y Y Y UC Y Y Y Y Y UC Y 9

Vermeulen 2010 Y Y Y Y Y Y Y UC Y UC Y 9

Villela 2010 UC UC Y N N N Y Y Y N Y 5

Voigt 2012 UC Y Y Y Y Y Y Y Y Y Y 10

Voigt 2011 UC Y Y Y N UC Y Y Y Y Y 8

Wang 2003 UC UC UC N N Y Y Y UC N N 3

Wilkinson 2012 Y Y Y N Y Y Y Y Y N Y 9

Xie 2010 UC UC Y N N Y Y Y Y Y N 6

Zarchi 2012 UC UC Y N N Y Y Y N N N 4

Note: Score of 8 or higher is considered high methodological quality. Abbreviations: N no, NA not applicable, UC unclear, Y yes.


Table 3: Results for high quality systematic reviews for which a meta-analysis was not conducted (N=16)

Author, year

# of studies

included

Intervention Comparator Conclusion

Leg ulcers (3 reviews)

Vermeule,2010

3 Wound dressings containing silver or with added silver

Dressing with silver at different dosages, no silver, other antiseptics

Silver-containing foam dressings did not significantly increase complete ulcer healing as compared with standard foam dressings or best local practice after up to four weeks of follow-up, although a greater reduction of ulcer size was observed with the silver-containing foam. The use of antibiotics was assessed in two trials, but no significant differences were found.

Nelson, 2009

1 Ketanserin ointment (2%) or 2 drops lavender and 1 drop German chamomile in half a teaspoon grape seed oil (6% solution).

Polyethylene glycol, standard care

There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers.

Aziz, 2011 3 EMT Sham EMT There is no high quality evidence that electromagnetic therapy increases the rate of healing of venous leg ulcers

Pressure ulcers (4 reviews)

McGinnis, 2011

1 Relief of pressure (Nimbus system)

Cairwave system One small study at moderate to high risk of bias was identified, which provided no evidence to inform practice.

McInnes, 2011

18 Pressure-relieving support surfaces

UC There is no conclusive evidence about the superiority of any support surface for the treatment of existing pressure ulcers.

Langer, 2008

4 500 mg ascorbic acid twice daily, very high protein, 3x200 mg zinc sulphate per day

10 mg ascorbic acid, high protein, placebo

It was not possible to draw any firm conclusions on the effect of enteral and parenteral nutrition on the prevention and treatment of pressure ulcers.

Bradley, 1999

35 Debridement methods UC, other debriding agents

No studies were found that compared debridement with no debridement. Without these studies it is unclear whether wound debridement is a beneficial


Author, year

# of studies

included


process that expedites healing and there is insufficient evidence to promote the use of one debriding agent over another. There was only a single comparison between two debriding agents that produced a significant result (hydrogel significantly reduced necrotic wound area compared with dextranomer polysaccharide paste).

Diabetes foot ulcers (3 reviews)

Nelson, 2006

23 All interventions including antibiotics (oral and IV), topical agents and G-CSF.

All comparators including antibiotic and topical agents.

The available evidence is too weak to be able to draw reliable implications for practice.

Hinchliffe, 2012

49 Revascularization (percutaneous transluminal angioplasty, vein bypass, endovascular plaque excision, popliteal inflow)

All comparators At 1-year follow-up, 60% or more ulcers had healed following revascularization with either open bypass surgery or endovascular revascularization. Studies appeared to demonstrate improved rates of limb salvage associated with revascularization compared with the results of medically treated patients in the literature. There were insufficient data, however, to recommend one method of revascularization over another.

Ubbink, 2008

7 Topical negative pressure

Gauze soaked in saline, dressings (hydrocolloid gel, cadexomer iodine, hydrogels, alignate, foam)

There is little evidence to support the use of topical negative pressure in the treatment of wounds.

Mixed acute and/or chronic wounds (1 review)

Dat, 2012 7 Aloe vera Placebo, other creams not containing aloe vera

There is currently an absence of high quality clinical trial evidence to support the use of aloe vera topical agents or aloe vera dressings as treatments for acute and chronic wounds.


Author, year

# of studies

included


Surgical wounds (3 reviews)

Smith, 2011

5 Debridement (surgical, biosurgical, autolytic, mechanical, chemical, enzymatic)

Placebo, an alternative method of debridement, any other therapy, no treatment

There is a lack of large, high-quality published RCTs evaluating debridement per se, or comparing different methods of debridement for surgical wounds, to guide clinical decision-making.

Lewis, 2001

17 Autolytic methods of debridement (foam dressings, alginate dressings, hydrocolloid dressings, dextranomer polysaccharide beads dressings)

Gauze or gauze based dressings, impregnated or otherwise

There is a suggestion that the debriding agents have a beneficial effect on healing compared to traditional gauze dressings. However, these results should be interpreted with caution due to the poor quality of the studies. In view of the lack of data and the poor methodological quality of the trials, there is no evidence to support the superiority of one type of the debriding agents dressing over another.

Vermeule,2012

13 Dressings and topical agents (foam, alginate, gauze -with or without a topical agent, bead dressing, hydrocolloids, plaster cast, aloe vera gel)

Other dressings, UC Wound healing: Whilst a single small trial of aloe vera supplementation versus gauze suggests delayed healing with aloe vera, the results of this trial are un-interpretable since there was a large differential loss to follow up. A plaster cast applied to an amputation stump accelerated wound healing compared with elastic compression. There were no statistically significant differences in healing for other dressing comparisons (e.g. gauze, foam, alginate; 11 trials). Hospitalization: Four trials showed no difference in length of hospital stay. One trial found shorter hospital stay in people after amputation when plaster casts were applied compared with elastic compression.

Infected wounds (1 review)

Adderley, 2007

2 Metronidazole gel or Miltefosine solution

Placebo There is weak evidence that a 6% solution of miltefosine, applied as a fluid to small, superficial fungating wounds on the breast, may slow down the progression of the disease.


Author, year

# of studies

included


Burns (1 review)

Storm-Versloot, 2010

26 Wound dressings or topical applications containing silver

Topical agent without silver, dressings without silver, alternative silver-containing dressings or topical preparations

There is not enough evidence to support the use of silver-containing dressings or creams, as generally these treatments did not promote wound healing or prevent wound infections. Some evidence from a number of small, poor-quality studies suggested that one silver-containing compound (silver sulphadiazine) has no effect on infection, and actually slows down healing in patients with partial thickness burns.

Abbreviations: EMT electromagnetic therapy, G-CSF granulocyte-colony stimulating factors, IV intravenous, UC usual care.


Table 4: Healing outcomes for reviews including venous and arterial leg ulcers (N=66 meta-analyses)

Intervention

Author, year

# of studies in MA

Comparator

Results of meta-analysis Conclusion

RR (95%CI) OR (95%CI) MD (95%CI)

Number/proportion of ulcers healed (44 meta-analyses)

4-layer compression bandage

O'Meara, 2009

4 Multi-layer short stretch bandage

1.12 0.96, 1.31

NR NR NR NR Not different*

O'Meara, 2009

2 Compression system with paste bandage as the base

1.34 0.78, 2.28


4-layer bandage Cullum, 2001

3 Other multilayer high compression bandages

1.02 0.87, 1.18


Compression stockings

Cullum, 2001

2 Compression bandage

1.39 1.00, 1.92

NR NR NR NR High compression stockings more effective than compression bandage*

Components including elastic bandage

O'Meara, 2009

2 Components including inelastic bandage

1.83 1.26, 2.67

NR NR NR NR Elastic bandage more effective than inelastic bandage*

Elastic multi-layer high compression bandages

Fletcher, 1997

3 Inelastic compression

NR NR 2.26 1.4, 3.7 NR NR Elastic multi-layer high compression bandage more effective than inelastic compression

Cadexomer iodine plus compression therapy

O'Meara, 2010

2 UC plus compression therapy

6.72 1.56, 28.95

NR NR NR NR Cadexomer iodine plus compression therapy more effective than UC plus


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

compression therapy*

Intermittent pneumatic compression

Fletcher, 1997

2 Compression stockings or Unna’s boot

NR NR 10.0 3.33, 33.80

NR NR Intermittent pneumatic compression more effective than compression stockings or Unna’s boot

Palfreyman, 1998

2 No intermittent compression

NR NR 8.45 0.63, 113.91

NR NR Not different

Nelson, 2011

3 Compression 1.09 0.91, 1.30


Multi-layer high compression

Cullum, 2001

5 Inelastic compression

1.08 0.79, 1.49


Cullum, 2001

4 Single-layer compression

1.41 1.12, 1.77

NR NR NR NR Multi-layer high compression more effective than single-layer compression*

Fletcher, 1997

4 Single layer systems

NR NR 2.2 1.3, 3.5 NR NR Multi-layer high compression more effective than single layer systems

Pentoxifylline with compression

Jull, 2011 7 Placebo 1.56 1.14, 2.13

NR NR NR NR Pentoxifylline with compression more effective than placebo*

Pentoxifylline without compression

Jull, 2011 4 Placebo 2.25 1.49, 3.39

NR NR NR NR Pentoxifylline without compression more effective than placebo*


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

2-component (outer elastic)

O'Meara, 2009

2 2-component (outer inelastic)

1.23 0.67, 2.25


2-layer stocking O'Meara, 2009

2 Short-stretch bandage

1.72 1.14, 2.58

NR NR NR NR 2-layer stocking more effective than short-stretch bandage*

Unna 's boot Palfreyman, 1998

3 Other therapies (unspecified)

NR NR 5.8 P=0.16 NR NR Not different

Laser (any) Flemming, 2008

2 Sham laser 1.21 0.73, 2.03


Autologous platelet rich plasma

Martinez-Zapata, 2012

2 UC with/without placebo

1.02 0.81, 1.27



2 UC with/without placebo

1.02 0.81, 1.27

NR NR NR NR Not different

High frequency US Cullum, 2011

6 No US 1.34 0.99, 1.80


Low frequency US Cullum, 2011

2 No US 3.91 0.47, 32.85


US Johannsen, 1998

5 No US NR NR NR NR 15.0 1.00, 30.00

US more effective than no US

Growth factor O’Donnell, 2006

8 Comparator 0.2 0.1-0.3 NR NR NR NR Not different

Honey

Jull, 2009 2 Control 1.15 0.96-1.38 NR NR NR NR Not different*

Foam dressing Palfreyman, 2007

2 Low adherent dressings

1.35 0.93, 1.94



Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Palfreyman, 2007

2 Foam dressing 1.2 0.77, 1.87


Hydrocolloid dressings

Bouza, 2005 8 Traditional dressing

0.99 0.85, 1.15


Bradley, 1999

8 Traditional dressing

NR NR 1.45 0.83, 2.54 NR NR Not different*

Bradley, 1999

2 Foam dressing NR NR 1.00 0.48, 2.08 NR NR Not different*

Palfreyman, 2007

8 Low adherent dressings

1.02 0.83, 1.25


Palfreyman, 2007

4 Foam dressing 0.98 0.79, 1.22


Palfreyman, 2007

3 Alginite dressing 0.72 0.15, 3.42


Palfreyman, 2007

3 Hydrocolloid dressing

1.56 0.67, 3.63


Palfreyman, 2007

2 Low adherent dressing

1.53 0.96, 2.42


Silver dressings

Chambers, 2007

2 Placebo/no treatment

1.79 0.19 , 17.11


Chambers, 2007

2 Placebo/no treatment

1.66 0.68, 4.05


Silver-impregnated dressing

Carter, 2010 7 Non-silver 0.02 0.01, 0.06


Topical negative Sadat, 2008 2 UC NR NR 1.93 1.05, 3.56 NR NR Topical negative


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

pressure pressure more effective than UC

Dermagraft Barber, 2008 2 Standard compression therapy

NR NR 4.48 1.01, 19.8 NR NR Dermagraft more effective than standard compression therapy

Artificial skin graft and standard wound care

Ho, 2005 3 UC 1.6 0.57, 4.46


Ciprofloxacin O'Meara, 2010

2 UC/placebo 1.72 0.57, 5.16


Zinc Wilkinson, 2012

4 Placebo 1.22 0.88, 1.68


Healing/improvement of ulcers (8 meta-analyses)

Stockings Amsler, 2009

8 Bandages NR NR 0.44 0.32, 0.61 NR NR Stockings more effective than bandages

Elastic high compression

Cullum, 2001

3 Multi-layer inelastic compression

1.54 1.19, 1,99

NR NR NR NR Elastic high compression more effective than multi-layer inelastic compression*

Granulocyte-macrophage colonystimulating factor

Hu, 2010 2 Placebo NR NR 6.5 2.15, 19.7 NR NR Granulocyte-macrophage colonystimulatingfactor more effective than placebo

Cryopreserved allografts

Jones, 2007 2 Dressing 1.62 0.79, 3.33



Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Tissue engineered skin

Jones, 2007 2 Dressing 1.51 1.22, 1.88

NR NR NR NR Tissue engineered skin more effective than dressing*

Cultured keratinocytes / epidermal grafts

Jones, 2007 4 Dressing 1.73 0.91, 3.28


Fresh allografts Jones, 2007 2 Dressing 2.06 0.54, 7.9 NR NR NR NR Not different*

Pentoxifylline Jull, 2011 11 All other treatments

1.7 1.30, 2.24

NR NR NR NR Pentoxifylline more effective than all other treatments*

Rate of ulcer healing (4 meta-analyses)

Polyurethane Bouza , 2005

3 UC 0.92 0.14, 1.98


Alginite Bouza , 2005

2 UC 1.1 0.86, 1.43


Micronized purified flavonoid

Coleridge-Smith, 2005

4 Placebo or standard compression

Reduction of RR 32%

3%, 70% NR NR NR NR Micronized purified flavonoid more effective than placebo or standard compression

4-layer bandage O'Meara, 2009

2 Compression system with paste bandage as the base

0.52 0.06, 0.97



Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Time to ulcer healing (5 meta-analyses)

Stockings Amsler, 2009

7 Bandages NR NR NR NR SMD -0.33

-0.50, -0.16

Bandages more effective than stockings

Micronized purified flavonoid


- Placebo or standard compression

Hazard ratio 1.33

P=0.0034 NR NR NR NR Micronized purified flavonoid more effective than placebo or standard compression

4-layer bandage O'Meara, 2009

5 Short stretch bandage

1.31 1.09, 1.58

NR NR NR NR 4-layer bandage more effective than short-stretch bandage*

O'Meara, 2009

4 Multi-layer short-stretch bandage

Hazard ratio 0.8

0.66, 0.97

NR NR NR NR 4-layer bandage more effective than multi-layer short-stretch bandage*

Topical negative pressure

Sadat, 2008 2 UC NR NR 1.93 1.05, 3.56 1.04 1.83, -0.25

Topical negative pressure more effective than UC

Ulcer size/area reduction (5 meta-analyses)

Silver treatments and silver-impregnated dressings

Carter, 2010 5 Placebo or conservative wound care, could not be another type of silver treatment

NR NR NR NR 10.29 3.86, 16.71

Silver treatments more effective than placebo or conservative wound care or non-silver therapies

Silver-impregnated dressing

Carter, 2010 3 Non-silver NR NR NR NR 0.01 -0.02, 0.05

Not different


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Micronized purified flavonoid fraction


5 Control (unspecified)

Reduction of RR 44%

7%, 94% NR NR NR NR Micronized purified flavonoid fraction more effective than control

US Johannsen, 1998

6 UC, placebo NR NR NR NR 14.50%

6.6, 22.3 US more effective than UC or placebo

Cadexomer iodine O'Meara, 2010

2 UC NR NR NR NR 0.47 0.26, 0.69

Cadexomer iodine more effective than UC*

Note: *these are high quality systematic reviews (AMSTAR ≥8). Abbreviations: CI confidence interval, MA meta-analysis, MD mean difference, NR not reported, OR odds ratio, RR relative risk, UC usual care, US ultrasound.


Table 5: Healing outcomes for reviews including pressure ulcers and sores (N=36 meta-analyses)

Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Ulcers/sores completely healed (25 MAs)

Collagenase debridement

MAS Ontario, 2009

2 Hydrocolloid occlusive dressing

1.33 0.80, 2.23 NR NR NR NR Not different

Dextranomer paste MAS Ontario, 2009

2 Hydrogel dressing


Hydrocolloid dressing

MAS Ontario, 2009

4 Traditional dressing

3.84 2.30, 6.41 NR NR NR NR Hydrocolloid more effective than traditional dressing

MAS Ontario, 2009

2 Povidine-soaked gauze


Hydrocellular dressing

MAS Ontario, 2009



Hydrogel dressing MAS Ontario, 2009


1.71 1.05, 2.79 NR NR NR NR Hydrogel more effective than hydrocolloid dressing

Hydropolymer dressing

MAS Ontario, 2009



Noncontact normothermic dressing

MAS Ontario, 2009

4 UC 1.31 0.86, 1.98 NR NR NR NR Not different


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Growth factor MAS Ontario, 2009

4 Placebo 2.29 0.52, 9.98 NR NR NR NR Not different

MAS Ontario, 2009


Recombinant PDGF (100mg/ml)

MAS Ontario, 2009

2 Placebo 4.43 0.48, 40.56


Recombinant PDGF (300 micro g/ml)

MAS Ontario, 2009

2 Placebo 2.17 0.06, 81.31


Polyurethane foam MAS Ontario, 2009

3 Hydrocolloid 1.18 0.85, 1.64 NR NR NR NR Not different

Low-air-loss beds Cullum, 2001

2 Foam overlay 1.25 0.84, 1.86 NR NR NR NR Not different*

MAS Ontario, 2009

2 Foam overlay 1.25 0.84, 1.86 NR NR NR NR Not different

Nimbus 3 AP mattress

MAS Ontario, 2009

2 Another AP mattress replacement/overlay


MAS Ontario, 2009

4 Another AP mattress in hospital setting

1.4 1.08, 1.80 NR NR NR NR Nimbus AP more effective than other AP mattresses in hospital


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

setting

Electrical stimulation

MAS Ontario, 2009

3 Placebo 3.08 0.58, 16.41


Electromagnetic therapy

MAS Ontario, 2009

3 Sham therapy 3.43 0.35, 33.61


Low-level laser therapy

MAS Ontario, 2009

3 UC 1.26 0.92, 1.95 NR NR NR NR Not different

MAS Ontario, 2009

3 Sham laser 1.17 0.85, 1.63 NR NR NR NR Not different

US Cullum, 2001

2 No US 0.97 0.65, 1.45 NR NR NR NR Not different*

Sari, 2006

2 Sham US 0.97 0.65, 1.45 NR NR NR NR Not different*

MAS Ontario, 2009

2 Sham US 0.97 0.65, 1.45 NR NR NR NR Not different

Zinc supplement MAS Ontario, 2009


Healing/improvement of ulcers/sores (7 MAs)

Hydrocolloid dressings

Bradley, 1999

5 UC NR NR 2.57 1.58, 4.18 NR NR Hydrocolloid more effective than UC*


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Polyurethane dressings

Bradley, 1999

4 Other dressings NR NR 0.8 0.44, 1.44 NR NR Not different*

Air-fluidized supports

Cullum, 2008

3 UC NR NR NR NR NR NR Air-fluidized supports more effective than UC (data NR)

Air-fluidized bed Cullum, 2004

2 Standard care 1.4 1.04, 1.88 NR NR NR NR Air-fluidized bed more effective than standard care*

MAS Ontario, 2009

2 Conventional mattress

1.4 1.04-1.88 NR NR NR NR Air-fluidized bed more effective than conventional mattress

Alternative foam mattress

Cullum, 2004

5 Standard foam mattress

0.4 0.21, 0.74 NR NR NR NR Alternative foam more effective than standard foam mattress*

Electrotherapy Cullum, 2001

2 Sham therapy 7.92 2.39, 26.31

NR NR NR NR Electrotherapy more effective than sham*

Healing rate of ulcers/sores (3 MAs)

Debridement agents

Cullum, 2008

32 Other debridement agent

NR NR NR NR NR NR Not different (data NR)

Hydrocolloid dressing

Cullum, 2008

6 Standard dressings

NR NR NR NR NR NR Not different (data NR)

AP mattresses Cullum, 2008

5 UC NR NR NR NR NR NR Not different (data NR)


Intervention

Author, year

# of studies in MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Incidence of pressure ulcers (1 MA)

Nutritional support Stratton, 2005

4 UC NR NR 0.75 0.62, 0.89 NR NR Nutritional support more effective than UC*

Note: *these are high quality systematic reviews (AMSTAR ≥8).Abbreviations: AP alternating pressure, CI confidence interval, MA meta-analysis, MAS Medical Advisory Secretariat, MD mean difference, NR not reported, OR odds ratio, PDGF platelet-derived growth factor, RR relative risk, UC usual care, US ultrasound.


Table 6: Healing and hospitalization outcomes for reviews including diabetes ulcers and infections (N=25 meta-analyses)

Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Ulcers completely healed/resolved (15 MAs)

Dermagraft Barber, 2008

3 Standard saline dressings

NR NR 1.78 0.92, 3.45

NR NR Not different

Skin replacement therapy

Blozik, 2008 5 UC NR NR 1.46 1.21, 1.76

NR NR Skin replacement therapy more effective than UC

Artificial skin graft with standard care

Ho, 2005 9 UC 1.4 1.21, 1.63

NR NR NR NR Artificial skin graft with standard care more effective than UC alone*

Fibrous-hydrocolloid dressing

Dumville, 2012a

2 Basic wound contact dressing

1.01 0.74, 1.38


Foam dressing Dumville, 2011a


2.03 0.91, 4.55


Dumville, 2011a

2 Alginate dressing

1.5 0.92, 2.44


Alginate dressing Dumville, 2012b


1.09 0.66, 1.80


Dumville, 2012b

2 Foam dressing 0.67 0.41, 1.08


Hydrogel dressing Dumville, 2011b

3 Basic wound dressing

1.8 1.27, 2.56

NR NR NR NR Hydrogel dressing more effective than basic wound dressing*


Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Edwards, 2012

3 Gauze/UC 1.84 1.30, 2.61

NR NR NR NR Hydrogel more effective than gauze with UC*

HBOT Kranke, 2012

3 Hyperbaric air/sham

9.53 0.44, 207.76


Roeckl-Wiedmann, 2005

2 Control 4.78 0.94, 24.24


G-CSF Cruciani, 2005

NR Placebo/UC NR NR NR NR NR NR Not different (data NR)

PRP Villela, 2010

4 Control (unspecified)

NR NR 7.7 2.94, 20.31

NR NR PRP more effective than control

CHM plus standard treatment

Chen, 2010 4 UC 0.62 0.39, 0.97

NR NR NR NR CHM more effective than standard therapy

Ulcer healing/ improvement (3 MA)

CHM Chen, 2010 3 UC 0.81 0.71, 0.92

NR NR NR NR CHM more effective than standard therapy


NR Placebo/UC NR NR NR NR NR NR Not different (data NR)

Cruciani, 2011

2 Placebo/UC 9.45 0.54, 164.49


Ulcer healing rate (1 MA)

UC Margolis, 1999

6 UC NR NR NR NR 30.9%

26.6, 35.1

Not different


Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Non-healing ulcers/no improvement (5 MAs)

CHM Chen, 2010 6 UC 0.34 0.21, 0.53

NR NR NR NR CHM more effective than UC

HA scaffold and keratinocytes

Voigt, 2012 2 UC 0.9 0.76, 1.07


HA derivative Voigt, 2012 2 UC 0.24 0.12, 0.49

NR NR NR NR HA derivatives more effective than UC*

LFLINU Voigt, 2011 2 Sharps debridement

0.74 0.58, 0.95

NR NR NR NR LFLINU more effective than sharps debridement*

LFHICU Voigt, 2011 2 Sharps debridement

0.64 0.46, 0.89

NR NR NR NR LFHICU more effective than sharps debridement*

Length of hospitalization (1 MA)


2 Control NR NR NR NR -1.4 days

-2.27, -0.53

G-CSF more effective than control*

Note: *these are high quality systematic reviews (AMSTAR ≥8).Abbreviations: AP alternating pressure, CHM Chinese herbal medicine, CI confidence interval, G-CSF granulocyte-colony stimulating factor, HA hyaluronic acid, HBOT hyperbaric oxygen therapy, LFHICU low frequency high intensity contact ultrasound, LFLINU low frequency low intensity noncontact ultrasound, MA meta-analysis, MD mean difference, NR not reported, OR odds ratio, PRP platelet-rich plasma, RR relative risk, UC usual care, US ultrasound.


Table 7: Healing outcomes for reviews including mixed acute and/or chronic wounds (N=17 meta-analyses)

Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Number/proportion of wounds healed (10 MAs) Hydrocolloid dressing

Bouza, 2005 6 Other modern dressings

1.13 0.86, 1.48


Singh, 2004 12 Conventional dressing

RD 0.02

0.19, 0.02

1.73 1.08, 2.78

NR NR Hydrocolloid dressings more effective than conventional dressings

US

Cullum, 2001

4 No US 1.44 1.01, 2.05


Cullum, 2001

4 Sham US 1.18 0.89, 1.54


Laser therapy Cullum, 2001

2 Sham 1.21 0.73, 2.03


Low-level laser therapy

Lucas, 2000 3 Placebo or any other intervention

0.76 0.41, 1.40


Apligraf and UC Ho, 2005 5 UC 1.71 1.34, 2.17

NR NR NR Apligrafmore effective than UC*

Dermagraft and UC Ho, 2005 6 UC 1.36 1.11, 1.66

NR NR NR NR Dermagraftmore effective than UC*

Any artificial skin graft and standard wound care

Ho, 2005 13 UC 1.44 1.22, 1.71

NR NR NR NR Any artificial skin graft plus standard wound care more effective than UC*


Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Autologous platelet-rich plasma


4 UC with/ without placebo

1.85 0.76, 4.51


Wounds not healed (1 MA) Tap water Fernandez,

2012 2 No cleansing 1.26 0.18,

8.66 NR NR NR NR Not different*

Time to healing (1 MA) Honey Jull, 2009 3 Control NR NR NR NR 1.55 -1.91,

5.00 Not different*

Ulcer size/area reduction or epithelialization (5 MAs) Silver dressings Lo, 2009 8 Non-silver

dressings NR NR NR NR 0.28 0.16, 0.39 Silver dressings more

effective than non-silver dressings*

Autologous platelet-rich plasma



51.78%

32.70%, 70.86%

NR NR NR NR Autologous platelet-rich plasma more effective than UC with or without placebo*



NR NR NR NR -1.94 -4.74, 0.86

Not different*


6 UC 1.4 0.58, 2.31


Topical negative pressure

Suissa, 2011 9 Standard wound care

0.77 0.63, 0.96


Note: *these are high quality systematic reviews (AMSTAR ≥8). Abbreviations: CI confidence interval, MA meta-analysis, MD mean difference, NR not reported, OR odds ratio, RD risk difference, RR relative risk, UC usual care, US ultrasound.


Table 8: Healing and hospitalization outcomes for reviews including wound infections (N=4 meta-analyses)

Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Treating infection (2 MAs) Fluoroquinolones (without concomitant antibiotics against anaerobics)

Falagas, 2006

14 Beta-lactam NR NR 1.29 1.00, 1.66

NR NR Fluoroquinolonemore effective than beta-lactam

Ciprofloxacin Falagas, 2006

8 Beta-lactam (ceftazidime andcefotaxime)

NR NR 2.49 1.45, 4.26

NR NR Ciprofloxacin more effective than beta-lactam

Wound resolution (1 MA)

Topical negative pressure/vacuum associated closure

Pan, 2010 6 UC NR NR 6.43 3.81, 10.85

NR NR Topical negative pressure/vacuum associated closure more effective than UC

Length of hospitalization (1 MA) Vacuum assisted closure

Damini, 2010

6 UC NR NR NR NR -7.18 days

-10.82, -3.54

Vacuum assisted closure more effective than UC

Abbreviations: CI confidence interval, MA meta-analysis, MD mean difference, NR not reported, OR odds ratio, RR relative risk, UC usual care.


Table 9: Healing outcomes for reviews including burns (N=4 meta-analyses)

Intervention

Author, year

# of studies in

MA

Comparator


RR (95%CI) OR (95%CI) MD (95%CI)

Healing rate (2 MAs)

GM-CSF Hu, 2010 2 Placebo NR NR NR NR 0.84 0.37, 1.3 Not different

GM-CSF on deep second-degree burns

Hu, 2010 2 Placebo NR NR NR NR 0.96 0.22, 1.69

Not different

Time to healing (2 MAs)

Honey Jull, 2009 3 Silver sulfadiazine

NR NR NR NR -4.37 days

-8.94, 0.19

Honey more effective than silver sulfadiazine*

Honey on partial-thickness burns

Jull, 2009 2 Conventional dressings

NR NR NR NR -4.68 days

-5.09, -4.28

Honey more effective than conventional dressings*

Note: *these are high quality systematic reviews (AMSTAR ≥8).Abbreviations: CI confidence interval, GM-CSF granulocyte-macrophage colony-stimulating factor, MA meta-analysis, MD mean difference, NR not reported, OR odds ratio, RR relative risk.


Table 10: Economic study summary characteristics

Characteristic # of cost studies (N=104 total)

% of cost studies

Year of publication 1982-1996 1997-2000 2001-2005 2006-2010

2011-present

15 14.4 24 23.1 24 23.1 33 31.7 8 7.7

Country of conduct Europe (22 of these are from the UK)

North America Asia

Australia& NZ South America& Caribbean

45 43.3 43 41.3 9 6.7 6 5.8 1 1.0

Study design CUA/CEA

CEA Costing

12 11.5 23 22.1 69 66.3

Sample size* 10-30 31-50

51-100 101-150 151-200 201-400

>400 (includes 2 RCTs and 2 SRs) Not reported

19 18.3 20 19.2 19 18.3 7 6.7 8 7.7

13 12.5 13 12.5 5 4.8

Patient population† Elderly

Chronic venous disease Diabetes

Surgical/trauma

62 59.6 29 27.9 22 21.2 12 11.5

Setting Inpatient/institutionalized

Outpatient clinic Home care

Mixed settings Not reported

38 36.6 16 15.4 19 18.3 23 22.1 8 7.7

Type of wound Venous ulcers

Diabetic ulcers/infection Pressure ulcers

Surgical wounds/infection Mixed wounds

Other wound infection

29 27.9 22 21.2 23 22.1 12 11.5 17 16.3 1 1.0

Interventions examined† Dressings

62 59.6


Characteristic # of cost studies (N=104 total)

% of cost studies

Cleansers Bandages/Stockings

Topical negative pressure Mattresses/off-loading devices

Skin replacement therapy Other surgical

Oral or IV treatments Programs/guidelines/systems

Biologic agents Nutritional/herbal supplementation

Hyperbaric oxygen/other device Larval therapy

Unspecified

1 1.0 6 5.8 7 6.7 8 7.7 3 2.9 8 7.7 8 7.7

24 23.1 2 1.9 3 2.9 8 7.7 2 1.9 1 1.0

Comparators examined† Standard/usual wound care

Placebo Dressings Cleansers

Bandages/Stockings Topical negative pressure

Mattresses/off-loading devices Skin replacement therapy

Other surgical Oral or IV treatments

Programs/guidelines/systems Biologic agents

Nutritional/herbal supplementation Hyperbaric oxygen/other device

Unspecified

28 26.9 4 3.8

38 36.5 0 0 3 2.9 5 4.8 6 5.8 0 0 4 3.8 5 4.8 7 6.7 0 0 0 0 1 1.0 2 1.9

Notes: *For modeling studies, this refers to the total sample size of the studies that the model data were estimated from, †numbers do not add up to 104 studies or 100%, as the cost studies contributed data to more than one category. Abbreviations: IV intravenous, NZ New Zealand, RCT randomized clinical trial, SR systematic review, UK United Kingdom.


Table 11: Results for costing studies (N=69)

First author, unit† year of

costing values*

Country, study

duration

Intervention/ Comparator

Total Cost [variation‡]

Intervention Cost [variation‡]

Personnel Cost [variation‡]

Hospital Cost

[variation‡]

Gary, US$ 1991

US, 36 weeks Home air-fluidized bed therapy including nurse specialist

16,415 NR NR 13,263 [NR]

UC (included alternating pressure pads, air-support mattresses, water mattresses, and high-density foam pads)

16,800 NR NR 25,736 [NR]

Mosher, US$ 1995

US, 4 weeks Collagenase 610.96 NR NR NR Autolysis 920.73 NR NR NR Fibrinolysin (fibrinolysin and desoxyribonuclease combined)

986.38 NR NR NR

Wet-to-dry saline dressings (mechanical debridement)

1008.72 NR NR NR

Motta, US$ 1999

US, 8 weeks Polymer hydrogel dressing (FlexigelAcryDerm Sheet)

57.76 19.05 NR NR

Hydrocolloid dressing (DuoDERM CGF) 91.48 47.35 NR NR Mulder, US$ 1995

US, 4 weeks or until 50% eschar removal

Hypertonic saline hydrogel (Hypergel) plus covered by polyurethane dressing (Alldress)

193.93 [SD88.63] 135.78 [SD 62.06] NR NR

Saline moistened gauze dressing, held by tape (standard wet-to-dry dressing)

NR NR NR NR

Narayanan, US$ 2005

US, until healed

Balsam Peru, hydrogenated castor oil, and trypsin ointment (Xenaderm)

NR NR stage 1 ulcers:50.8 [95% CI 47.1-54.4]; stage 2: 58.1 [95% CI 53.5-62.8]

NR

Balsam Peru, hydrogenated castor oil, and trypsin + other treatments (not necessarily simultaneously used)

NR NR stage 1: 54.5 [95% CI 48.9-60.1]; stage 2: 63.4 [95% CI 60.0-66.8]

NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

Other treatments NR NR stage 1: 61.7 [95% CI 58.7-64.7]; stage 2: 62.3 [95% CI 60.7-63.9]

NR

Sanada, Yen 2007

Japan, 3 weeks Hospital incentive system including wound, ostomy, continence nurses

65,310.5 [SD 36,675.1]

NA 57,277.9 [SD 33,842.9]

NA

Hospital without incentive system 66,936.6 [SD 60,535]

NA 55,421.8 [SD 56,190.2]

NA

Schulze, £ 2000

Germany, 4 weeks or less

Hydropolymer dressing 125.73 NR NR NR Alginate dressing plus film dressing 174.09 NR NR NR Alginate dressing plus sterile swab 142.03 NR NR NR

Sebern, US$ 1989

US, 8 weeks Transparent film dressing grade II: 845; grade III: 1470

NR NR NR

Gauze grade II: 1359; grade III: 1412

NR NR NR

Shalom, 2008 US$

Israel, 4 weeks (median 12 days)

Homemade negative pressure device NR 1.35 per day NR NR Vacuum-assisted closure system $22 during

hospitalization[devices costing $7000–9000]

NR NR NR

Shinohara, Yen 2008

Japan, 1 week Occlusive hydrocolloid dressing 714.9 [SD 262.8] NR NR NR Gauze dressing 779.9 [SD 345.3] NR NR NR

Sotto, € 2003-2007

France, tx duration

Guidelines in hospital for management of DFIs

232 NR NR NR

Before implementation of guidelines 823 NR NR NR Stotts, US$ 1997

US, mean 4.2 days

Clean dressings 12.38/dc [SD 5.8] NR NR NR Sterile dressings 21.97 [12.8] NR NR NR

Tan, NZ$ 1993 NZ, until healed (range 0-2 weeks)

Zenoderm (semi-occlusive hydrogel) 16.16 NR NR NR DuoDERM E (occlusive hydrocolloid) 36 NR NR NR

Taylor, £ 1987 UK, 12 weeks 4-layer high compression bandage 116.87 [range 52.63–261.74]

NR 62.22 [range 29.25–126.23]

NR

Standard home care without high compression bandages

240.28 [range 74.65–588.05]

NR 111 [range 41.65–272.83]

NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

Terry, US$ 2009

US, NR Telemedicine with wound care specialist consults

4021.84 NR NR NR

Wound care specialist consults 1937.01 NR NR NR UC at home 2595.68 NR NR NR

Tice, US$ 2005

US, mean 8 days

Ertapenem 355.55 [SD172.8] NR NR NR Piperacillin/Tazobactam 502.76 [SD

236.33] NR NR NR

Ukat, € 2003 Germany, 12 weeks

Multilayer elastic compression (Profore) bandage

587 46.37 7 NR

Short-stretch compression (Comprilin) bandage

1345 19.37 7 NR

Vickery, £ 1993

UK, until healed

District-wide leg ulcer service 15.74/ulcer NR NR NR before the leg ulcer service 17.95 NR NR NR

Villasin, US$ 1996

US, until healed

Dermagran spray + Dermagran ointment, mean 15 days

104.75 [SE12.92] 4.65 [SE 0.57] 100.1 [SE 12.35] NR

Saline spray + topical triple-antibiotic ointment, mean 48 days

323.23 [SD 171.7] 11.23 [SD 5.97] 312 [SD 165.75] NR

Vogt, € 2007 Denmark, 4 days

Aquacel (occlusive moist) dressing NR [20.3-48.7] NR NR NR Mepore (viscose self-adhesive) dressing NR [10-11.8] NR NR NR

Wayman, £ 2000

UK, 4 weeks or until debrided

Larval therapy, 3 days 78.64 NR 10.77 NR Hydrogel dressing, max. 1 month 136.23 NR 53.85 NR

Wynne, AU$ 2004

Australia, 2-5 days

Dry absorbent dressing (Primapore) NR 0.52 [IQR 0.52-0.52]

NR NR

Hydrocolloid dressing (Duoderm Thin) NR 3.93 [IQR 3.93-7.86]

NR NR

Hydroactive dressing (Opsite) NR 1.59 [IQR 1.59-3.18]

NR NR

Xakellis, US$ 1990

US, until healed (median 10 days)

Hydrocolloid dressing 15.58 [25%, 75% 12.04, 30.22]

13.32 [25%, 75%10.27, 25.70]

2.26 [25%, 75%1.78, 4.52]

NR

Saline gauze dressing 22.65 [25%, 75% 13.54, 53.56]

3.97 [25%, 75% 2.84, 9.46]

18.67 [25%, 75% 10.84, 44.09]

NR

Abidia, £ 2000 UK, 1 year Hyperbaric oxygen therapy 4972/px 3000 NR 1972/dc Hyperbaric air 7946/px NR NR 7946/dc

Akagi, US$ Japan, NR Sterilize surgical wound and change gauze 61.80/ulcer healed 61.80 NR NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

2003 dressing,1 week sterilize surgical wound and change gauze dressing, 2 days

14.70 14.70 NR NR

Albert, US$ 2008

US, 2 weeks Negative Pressure Wound Therapy (foam-based dressing)

365.42 [range 152.37, 819.18]

195.25/dc [range 152.37, 359.42)]

NR NR

Negative Pressure Wound Therapy (gauze-based dressing)

310.78 [range 282.98, 406.21]

255.75/dc [range 141.49, 310.78]

NR NR

Apelqvist, SEK 1990

Sweden, until healed/ amputation

Primary ulcer healing without amputation 51000 [range 3000 – 808000]

NR NR NR

Major amputation 390105 NR NR NR Minor amputation 258320 NR NR NR Primary amputation 288931 NR NR NR Re-amputation 445678 NR NR NR Healing with amputation 344000 [range

27000 – 992000] NR NR NR

Bale, £ 1994 UK, 8 weeks or until healed

Hydrocellular dressing (all ulcers) 2980 NR NR NR Hydrocolloid dressing (all ulcers) 2692 NR NR NR Hydrocellular dressing (leg ulcer) 1290 NR NR NR Hydrocolloid dressing (leg ulcer) 932 NR NR NR Hydrocellular dressing (pressure ulcer) 844 NR NR NR Hydrocolloid dressing (pressure ulcer) 1142 NR NR NR Hydrocellular dressing (other ulcer) 846 [ NR NR NR Hydrocolloid dressing(other ulcer) 618 NR NR NR

Bosanquet, £ 1991

UK, 12 weeks Hospital-based venous ulcer care clinics 433600/yr 1334.40/yr NR NR Six community leg ulcer clinics 169000/yr 867.20/yr NR NR

Braakenburg, € 2004

Netherlands, until healed

Vacuum-assisted closure, median 16 days 353 [range 113, 1503]

for material 259 [range 86, 1297]

81 [range 21, 282] NR

Modern wound dressings (AlgiSite, Cutinova-Foam, Cutinova-Cavity), median 20 days

273 [range 40, 1123]

for materials 94 [range 16, 431]

176 [range 16, 750]

NR

Branom, US$ 2001

US, 8 weeks Pressure Guard (Constant Force Technology) mattress

1080 (buy mattress)

NR NR NR

Low Air Loss mattress, 8 weeks 1960 (rent mattress)

NR NR NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

Burgos, Pts 1998

Spain, 12 weeks

Collagenase Ointment (Iruxol) 41488 [95% CI 26191, 56784]

20845 [95% CI 10420, 31269)]

16093/px [95% CI 9977, 24300)]

NR

Hydrocolloid dressing (Varihesive) 32963 [95%CI 23389, 42538]

20971 [14098, 27845)]

9045/px [95% CI 6874, 11848)]

NR

Cannavo, AU$ 1996

Australia, 38 days (SD 7.8)

Calcium Alginate Dressing 15.25/day 12.94/day NR NR Sodium Hypochlorite dressing 19.36/day [95%CI

0.35, 8.58)] 11.54/day NR NR

Combined dressing pad 14.14/day [95%CI 5.49, 3.29)]

8.78/day NR NR

Capasso, US$ 2003

US, 7 weeks Wet-to-dry normal saline gauze dressing 3774 133 3641 NR Amorphous hydrogel dressing 2634 180 2454 NR

Carls, US$ 2008

US, 1 year prior to ulcer

Podiatric medical care (Commercial insurance)

48318 NR NR NR

No podiatric medical care (Commercial insurance)

61792 NR NR NR

Podiatric care (Medicare) 38668 NR NR NR No podiatric care (Medicare) 43537 NR NR NR Amputation (Commercial insurance) 110530 NR NR NR No amputation (Commercial insurance) 50733 NR NR NR Amputation (Medicare) 79658 NR NR NR No amputation (Medicare) 39578 NR NR NR

Chang,RM 1997

Malaysia, 8 weeks or until healed

Hydrocellular dressing (DuoDERM CGF) 271.45 NR 45.89 NR Saline gauze dressing 173.05 NR 105.30 NR

Cherry, £ 2004 UK, mean 15 weeks

Vibro-Pulse (24-volt cycloidal vibration) and standard compression bandages

1590 180 1140 NR

Standard dressing and compressive bandaging (no vibration therapy)

9416 1284 8132 NR

Chuangsuwanich, US$ 2011

Thailand, 8 weeks

Silver mesh dressing (Tegaderm) US$ 263 NR NR NR Silver sulfadiazine cream US$ 1812 NR NR NR

Clay, US$ 2004

US, 96 hours IV ceftriaxone and metronidazole NR 18.71/day NR NR Ticarcillin/clavulanate potassium NR 30.56/day NR NR

DePalma, US$ 1998

US, 12 weeks Unna'sboot 901.73 [SD576.45] 160.86 [SD 96.86] 331.37 [SD 255.75]

NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

Theraboot 559.41 [SD290.75] 122.79 [SD 27.59] 201.91 [SD131.17]

NR

Fujimoto, Yen 2007

Japan, NR Hydrocolloid dressing (Karayahesive) NR 340 NR NR Conventional gauze and tape dressing NR 83 NR NR

Gibbons, US$ 1984 and 1990

US, NR Team changes emphasizing aggressive surgical limb revascularization

1990: 19594 15981 NR NR

Conventional approach (non-aggressive vascular surgical approach)

1984: 21323 19808 NR NR

Granick, US$ 2003

US, during hospital stay

Wound debridement using Versajet Net cost savings of 1900/px

NR NR NR

Conventional sharp debridement 3393/procedure NR NR NR Greer, US$ 1988

US, NR Air-fluidized therapy support system 16352.80 5760.00 112.80 10480.00 Conventional hospital bed 23211.50 1080.00 7721.50 14410.00

Hansson, US$ 1994

Sweden, UK, Denmark, Netherlands, 12 weeks

Cadexomer iodine paste 517.30 [range 321.00, 845.90]

7.79/dc (Sweden) 12.00 (nurse - Sweden)

NR

Hydrocolloid dressing 480.30 [range 96.90, 935.10]


NR

Parrafin gauze dressing 581.70 [range 283.80, 1043.50]


NR

Hiskett, £ 2008 UK, 2 - 74 days

Topical negative pressure in hospital 628.2 [SD671.90] NR NR 34/day [SD 2.8]

Topical negative pressure at home 628.2 [SD 371.10] NR NR 45.9/day [SD 17.0]

Horswell, US$ 1999

US, 1 yr Staged management foot care 4776 NR NR NR Standard foot care 9402 NR NR NR

Hurd, CAN$ 2006

Canada, 1 yr Comprehensive community wound care 4952 1714 3239 NR UC 17575 1204 16371 NR

Junger, DM2008

Germany, until healed

Low-frequency pulsed current (Dermapulse)

13967/ulcer NN NR NR

Placebo electrostimulation 17425/ulcer NR NR NR Kerstein, US$ 2000

US, 12 weeks Saline gauze (pressure ulcer) NR 92.43 1335.37 NR Hydrocolloid C dressing (pressure ulcer) NR 270.50 509.24 NR Hydrocolloid D dressing (pressure ulcer) NR 260.06 490.50 NR Impregnated gauze (venous ulcer) NR 111.97 1269.07 NR



costing values*

Country, study

duration





Hospital Cost

[variation‡]

Hydrocolloid D (venous ulcer) NR 223.23 937.71 NR Human skin construct (venous ulcer) NR 6130.02 848.57 NR

Kerstein, US$ 2000

US, until healed

Hydrocolloid dressing 4700/ulcer NR NR NR Unna's boot 8200/ulcer NR NR NR Saline gauze dressing 2500/ulcer NR NR NR

Kerstein, US$ 2000

US, 12 weeks Hydrocolloid dressing (Protocol D, or DuoDerm)

NR 265 230 NR

Human skin construct (Apligraf) NR 7021 138 NR Saline gauze dressing NR 93 560 NR

Kikta, US$ 1998

US, until healed

DuoDermhydroactive dressing (HD) NR 14.24/week [SD 1.63]

NR NR

Unna's boot NR 11.76/week [SD 0.59]

NR NR

Lafferty, £ 2011

UK, 20 weeks Oxyzyme (enzyme containing hydrogel) NR 85.40/week/ulcer 36.00/hour NR lodozyme (an enzyme containing hydrogel) NR 85.40 NR NR UC NR 76.80/week/ulcer 36.00/hour NR

Lavery, US$ 2007

US, 20 weeks Negative pressure wound therapy 16733.00 NR NR NR Wet-to-moist dressing therapy 15258 (1nurse

visit/day); 28691 (2 nurse visits/ day)

NR NR NR

Levy, ₣ 1996 France, until healed (max. 6 months)

Debridement and dressings 6697 NR NR 1167 Debridementwithout dressings 4864 NR NR 0 Dressings without debridement 4385 NR NR 739

Luckraz, US$ 2003

UK, NR Vacuum-assisted closure (VAC) 16400 NR NR NR Sternal rewiring and irrigation 20000 NR NR NR

McIsaac, CAN$ 2000

Canada, 10 months

Home care wound management protocol 540.38/month NR NR NR UC 1487.02/month NR NR NR

McKinnon, US$ 1994

US, until healed

Ampicillin/ Sulbactam 14084 NR NR NR Imipenem/ Cilaststin 17008 NR NR NR

Nasar, £ 1982 UK, NR Debrisan 1053.05 84.05 NR 969.00 Eusol and paraffin 1667.00 66.00 NR 1601.00

Nather, SGD 2007

Singapore, 2002 to 2007

Multidisciplinary team with clinical pathway

NR NR NR 7698.98

UC NR NR NR 8847.17



costing values*

Country, study

duration





Hospital Cost

[variation‡]

O'Brien, € 2003

Ireland, 12 weeks

4-layer bandage NR NR 99.6 (nurse) NR UC NR NR 144.2 (nurse) NR

O'Brien, US$ 1999

US, NR Home care wound management NR [range 145, 300/week]

NR [range 75, 150/week]

54/nurse visit 16/office visit

Formal health facility care as an inpatient NR [range 2800, 6300/week]

NR NR NR

Ohlsson, SEK 1994

Sweden, 6 weeks

Hydrocolloidal dressing (DuoDERM) 1565 653 912 NR Saline soaked gauze dressing 4126 608 3518 NR

Perez, HTG 2010

Haiti, until healed

Wet dressing (0.9% saline soaked gauze) 271 [range 264, 284]

50 [range 23, 58] 105 [range 97, 119]

121 [range 118, 132]

Homemadewound vacuum-dressing system 360 [range 343, 370]

81 [range 62, 101] 188 [range 178, 198]

83 [range 72, 97]

Philbeck Jr., US$ 1999

US, NR Low-air-loss therapy 23465 NR NR NR Negative pressure wound therapy 14546 NR NR NR

Rerkasem, US$ 2009

Thailand, until healed

Diabetic foot protocol 1127.02 [SE1762.51]

NR NR NR

UC 1824.58 [SE 2239.3]

NR NR NR

Robson, US$ 2009

US, 5 weeks Recombinant basic fibroblast growth factor 2200/ulcer NR NR NR Placebo 3000/ulcer NR NR NR

Seretariat, CAN$

Canada, NR Hyperbaric oxygen therapy 6200/tx NR NR NR Amputation 60000/tx NR NR NR

Notes:*Publication date is used where year of values was not reported in the publication, †units are average cost per patient for the study period (unless otherwise noted), ‡variation is blank if not reported by the study authors. Abbreviations: AU Australia, CI confidence interval, dc dressing change, DFI diabetic foot infection, DM Deutsche Mark, HTG Haitian Gourde, IQR interquartile range, IV intravenous, MAX maximum,NR not reported, NZ New Zealand, Pts Spanish Peseta, px patient, RM Ringgit Malaysia, SD standard deviation, SE standard error, SEK Swedish Kronor, SGD Singapore Dollar, tx treatment,UK United Kingdom, UC usual care, US United States, yr year.


Table 12: Cost-effectiveness/cost-utility analyses methodological quality

STUDY

Q1 (well-

defined)

Q2 (alter-

natives)

Q3 (effective-

ness)

Q4 (all costs)

Q5 (measure-

ment)

Q6 (valuat-

ion)

Q7 (discount-

ing)

Q8 (incre-mental)

Q9 (sensitivity)

Q10 (discussion) TOTAL #

Yes Apelqvist 2008 Y Y N Y Y Y Y Y Y Y 9 Apelqvist 1996 Y Y N Y Y Y NA Y Y N 7 Augustin 1999 Y Y N Y Y Y Y Y N Y 8 Chuck 2008 Y N Y Y Y Y Y Y Y Y 9 Clegg 2007 Y N N Y Y Y NA Y Y N 6 Colwell 1993 Y Y N Y Y Y NA N N Y 6 Dumville 2009 Y Y Y Y Y Y Y Y Y Y 10 Edmonds 1999 Y Y N Y Y Y Y Y N Y 8 Ferrell 1995 Y Y N N Y Y Y Y Y Y 8 Foglia 2012 Y N N N Y Y Y Y Y Y 7 Glinski 1999 Y Y N Y Y Y Y Y N N 7 Gordon 2006 Y Y N Y Y Y Y Y Y Y 9 Graumlich 2003 Y Y N N Y Y Y Y Y N 7 Guest 2012 Y N N Y Y Y Y Y Y Y 8 Guo 2003 Y N N N Y Y Y Y Y Y 7 Habacher 2007 Y N N Y Y Y Y Y Y Y 8 Harris 2008 Y Y N N Y Y N Y N N 5 Iglesias 2006 Y Y Y Y Y Y Y Y Y Y 10 Iglesias 2004 Y Y Y N Y Y Y Y Y N 8 Jansen 2009 Y Y Y Y Y Y Y Y Y Y 10 Jeffcoate 2009 Y Y N Y Y Y NA Y N Y 7 Jull 2008 Y Y Y Y Y Y NA Y N Y 8 Michaels 2009 Y Y Y Y Y Y Y Y Y Y 10 Morrell 1998 Y Y Y N Y Y N Y Y Y 8 Muller 2001 Y Y N Y Y Y NA Y Y N 7 O'Brien 2003 Y Y Y Y Y Y NA Y N N 7 Oien 2001 Y Y N Y Y Y NA Y N Y 7 Patanwala 2007 Y Y N Y Y Y Y Y Y N 8 Payne 2009 Y Y N N Y Y Y Y Y N 7 Persson 2000 Y N Y Y Y Y Y Y Y Y 9 Piaggesi 2007 Y Y N N Y Y NA Y N Y 6 Sibbald 2001 Y Y N Y Y Y NA Y Y Y 8 Ubbink 2008 Y Y Y Y Y Y NA Y N Y 8 Vu 2007 Y Y Y Y Y Y NA Y Y Y 9 Watson 2011 Y Y N Y Y Y Y Y Y N 8


Table 13: Cost-effectiveness/cost-utility analyses results for venous ulcers (N=14)

Interventions

Study (study type,

country, currency, year

of values, perspective, sample sizea,

duration/ horizon)

Comparators Conclusion Traditional

home based treatment

Pinch grafting in hospital

Standard compression with external

treatments

Short-stretch high

compression bandages

Four-layer high


Vaseline gauze

dressing

Standard debride-

ment (Hydrogel)

Ulcer clinics using four-layer high compression bandaging

Morrell et al. (CEA, UK, £, 1995, health-care system, 233, 1 yearb)

For a gain of an additional week without an ulcer, it costs an extra £2.46 per px (ICER: £2.46 per ulcer-free week gained)

Intervention was more effective yet more costly than usual care*

Pinch grafting surgery conducted in primary care

Oien et al. (CEA, Sweden, £, 1997, NR, 58, 12 weeks)

Intervention was significantly less costly (£3876 saved per px healed) with similar healing rate (31%)

Intervention had similar effectiveness & was less costly compared to pinch grafting in hospital

Micronised Purified Flavonoid Fraction plus standard therapy

Glinski et al. (CEA, Poland, €, 1998, healthcare system, 140, 24 weeks)

ICER: - €849.58 per ulcer healed

Intervention was more effective &less costly than conventional care alone

Low-dose ultrasound plus standard care

Watson et al. (CUA/CEA, UK, £, 2007, healthcare system, 337, 12

No statistically significant difference in healing rates

Intervention had similar effectiveness and was more costly compared to standard care alone


Interventions

Study (study type,



duration/ horizon)





treatments

Short-stretch high


Four-layer high


Vaseline gauze

dressing

Standard debride-

ment (Hydrogel)

weeksb) or QoL Skin protectant DBCc plus compression with dressings; vs. skin protectant NSFBd plus compression with dressings

Guest et al. (CUA/CEA, UK, £, 2009/ 2010, health-care system, 510, 6 monthsb)

NSFB had statistically greater reduction in wound size. DBC had no statistically significant differences from control group

NSFB was more effective &had similar costs than the other 2 groups. DBC had similar costs & similar effectiveness to comparator

Pentoxifylline plus usual caree

Iglesias & Claxton (CUA/CEA, UK, £, 2004, healthcare system, 434, 1 year)

Intervention had £98 cost savings and 6.55 ulcer-free weeks gained per px

Intervention was more effective &less costly than the comparator*

Four-layer high compression bandages

Iglesias et al. (CUA/CEA, UK, £, 2001, healthcare system, 387, 1 year)

Intervention group had a significantly higher probability of healing

Intervention was more effective and less costly than the comparator*

O’Brien et al. (CEA, Ireland, €, NRf, health-care system, 200, 12 weeks)

Intervention had 20% better healing rate and €25 cost savings per px

Intervention was more effective and less costly than the comparator*


Interventions

Study (study type,



duration/ horizon)





treatments

Short-stretch high


Four-layer high


Vaseline gauze

dressing

Standard debride-

ment (Hydrogel)

Calcium alginate dressings with manuka honey (ApiNate UMF 12+) plus compression bandaging

Jull et al. (CEA, New Zealand, NZ$, NRg, health-care system, 368, 12 weeks)

No statistically significant differences in healing outcomes. Intervention was lessh costly (by NZ$55.68 per px)

Intervention had similar effectiveness compared to usual care & cost analysis was inconclusiveh*

Silver antimicrobial dressings plus compression bandages

Michaels et al. (CUA/CEA, UK, £, 2007, healthcare system, 213, 12 weeksb)

ICER: £489,250 per QALY gained

Intervention had similar effectiveness &was more costly compared to low-adherence dressings plus compression bandages*

Skin substitute (Apligraf) plus four-layer high compression bandage

Sibbald et al. (CEA, Canada, CAN$, 1996-1997, society, 293i, 3 months)

For a gain of an additional day without an ulcer, it costs an extra $14 per px (ICER: $14 per ulcer-free day gained)

Intervention was more effective yet more costly than comparator alone

Hydrocolloid dressing (Comfheel or

Augustin (CUA/CEA, Germany, DM,

Intervention had DM1139

Intervention had similar effectiveness &was less costly


Interventions

Study (study type,



duration/ horizon)





treatments

Short-stretch high


Four-layer high


Vaseline gauze

dressing

Standard debride-

ment (Hydrogel)

Varihesive)

NRj, NR, 25, 6 months)

cost savings per px

compared to Vaseline gauze

Larval therapyk

Dumville et al. (CUA/ CEA, UK, £, 2006, health-care system, 267, 6-12 months)

Intervention had similar health outcomes (but debrided faster)

Intervention had similar effectiveness &similar costs compared to Hydrogel debridement*

Lindsay Leg Club modell

Gordon et al. (CEA, Australia, €, 2005, society, 56, 6 months)

For a gain of an additional ulcer healed, it costs an extra €318 (ICER: €318 per ulcer healed)

Intervention was more effective yet more costly than home nursing

Notes:aFor modeling studies, this refers to the total sample size of the studies that the model data were estimated from, bOr less (i.e. until wound healed), cCavilon Durable Barrier Cream (DBC), dCavilon No Sting Barrier Film (NSBF), eThe comparator also included a placebo, fTrial conducted in 1999-2000; publication date 2003, gTrial conducted in 2004-2005; publication date 2008, hMean total cost was less for Intervention group due to 3 fewer hospitalizations but Authors concluded Intervention was probably generally more expensive, iThe RCT included in the model was not directly comparable, jPublication date 1999, kCost-effectiveness was reported for pooled loose & bagged groups, lUlcer care provided in an informal ‘drop-in’ centre promoting social interaction, *Denotes from a higher quality CEA/CUA. Abbreviations: CAN Canadian, CEA cost-effectiveness analysis, CUA cost-utility analysis, DM Deutsche Marks, ICER incremental cost-effectiveness ratio, NR not reported, NZ New Zealand, PX patient, QALY quality-adjusted life year, QoL quality of life, UK United Kingdom.


Table 14: Cost-effectiveness/cost-utility analyses results for pressure ulcers (N=7)

Interventions

Study (study type,

country, currency, year of

values, perspective, sample sizea,

duration/ horizon)

Comparators Conclusion Moist gauze

dressing (saline) Conventional foam

mattress Conventional

simple and saline dressings

Hydrocolloid (DuoDerm)

Usual nursing care

Hydrocolloid wafer dressing (DuoDERM CGF)

Colwell et al. (CEA, USA, US$, 1989-1990, NR, 94, mean 17 daysb)

Intervention saved nursing time due to less frequent dressing changes

Intervention was more effective & less costly than saline gauze

Low-Air-Loss Bed (Kinair Bed)

Ferrell et al. (CEA, USA, US$, 1992, provider, 84, median 33 & 40 days per group)

For mild ulcers and good healing characteristics, to gain an additional day without an ulcer it costs an extra$26 (in 1st year)

Intervention was more effective & more costly than Comparator

Advanced dressings

Foglia et al. (CEA, Italy, €, 2010, healthcare system, 362, 30 days)

Intervention group had a greater reduction in ulcer size (an additional 6% decrease)

Intervention was more effective & less costly than conventional simple dressings

Type I collagen (Medifil, Kollagen)

Graumlich et al. (CEA, USA, US$, 2001, provider, 65, 8 weeksc)

No statistically significant differences in healing outcomes

Intervention had similar effectiveness yet was more costly compared to Hydrocolloid

Self-adhesive polyurethane foam dressing (Allevyn Thin)

Payne et al. (CEA, USA, US$, 2006-2007, health-care system, 36, 4 weeksc)

Intervention saved $118/ week per px compared to Comparator (95% CI: $13, $223)

Intervention had similar effectiveness & was less costly compared to saline gauze


Interventions

Study (study type,



duration/ horizon)

Comparators Conclusion Moist gauze

dressing (saline) Conventional foam

mattress Conventional

simple and saline dressings

Hydrocolloid (DuoDerm)

Usual nursing care

Collagenase containing ointment (Novuxol) plus paraffin gauze (Jelonet) and absorbent bandages after saline

Muller et al. (CEA, The Netherlands, NLG, 1998, provider, 24, mean 11 & 14 days per group)

11 of 12 patients were completely healed in Intervention group versus 7 of 11 in Comparator group

Intervention was more effective & less costly than Hydrocolloid

Multi-disciplinary community wound care teamd,e

Vu et al. (CEA, Australia, AU$, 2000, healthcare system, 176f, max. 6 months)

The cost of training of AU$14.2 per wound was offset by a saving of AU$263.7 per wound

Intervention was more effective & less costly than usual nursing care*

Notes: aFor modeling studies, this refers to the total sample size of the studies that the model data were estimated from, bRange: 8-56 days, cOr less (i.e. until wound healed), dMost patients had pressure ulcers (78% & 75% in Intervention & Comparator groups, respectively) and the rest had uncomplicated leg ulcers, eConsisting of trained community pharmacists and nurses who undertook a wound management training course and applied a standardized treatment protocol developed for the study. Nurses and pharmacists in the control arm received no wound care training and the pharmacists were not involved in wound management, f176 participants with 342 total ulcers studied, *Denotes from a higher quality CEA/CUA. Abbreviations: AU Australian, CEA cost-effectiveness analysis, CI confidence interval, max maximum, NLG Dutch Guilders, NR not reported, px patient, US United States, USA United States of America.


Table 15: Cost-effectiveness/cost-utility analyses results for surgical wounds (N=3)

Interventions

Study (study type,



duration/ horizon)

Comparators Conclusion Standard moist wound therapy

(alginates, hydrocolloids, foams, or hydrogels)

Gauze dressings (dry, moist, or paraffin gauzes)

IV vancomycin during hospitalization and after

discharge: 11 d. in hospital and 3 d. after discharge

Negative pressure wound therapy (Vacuum-Assisted Closure System)

Apelqvist et al. (CEA, US, US$, 2005, health-care system, 162, 16 weeks max.b)

Intervention had a statistically significant higher proportion of wounds healed versus Comparator (55.8% vs. 38.8%)

Intervention was more effective & less costly than moist wound therapy

Occlusive moist-environment, nongauze-based materials (foams, alginates, hydrogels, hydrocolloids, hydrofibers, and films)

Ubbink et al. (CEA, The Netherlands, US$, 2005, NR, 285c, 6 monthsb)d

Intervention had higher total cost for local wound care per patient per day during hospitalization versus Comparator (US$11.74 vs. US$6.25)

Intervention had similar effectiveness yet was more costly compared to gauze dressings*

Intervention A - Oral linezolid during hosp-italization and after discharge: 8 d. in hospital and 6 d. after discharge. Intervention B - IV vancomycin during hospital-

Patanwala et al. (CEA, US, US$, provider, 2006, 41, 14 days total)

Intervention A was the most cost-effective. Intervention B (IV vancomycin during hospitalization followed by oral linezolid after discharge) would be was the most cost-effective only if the length of hospitalization was less than 6 days or if the probability of cure with oral

Oral linezolid during hospitalization and after discharge (Intervention A) was the most cost-effective of the 3 groups. The Comparator (IV vanco-mycin during hospital-ization and after discharge) was the least cost-effective of the 3 groups.


Interventions

Study (study type,



duration/ horizon)

Comparators Conclusion Standard moist wound therapy

(alginates, hydrocolloids, foams, or hydrogels)

Gauze dressings (dry, moist, or paraffin gauzes)

IV vancomycin during hospitalization and after

discharge: 11 d. in hospital and 3 d. after discharge

ization followed by oral linezolid after discharge: 8 d. in hospital and 6 d. after discharge.

linezolid (Intervention A) was less than or equal to 72%.

Notes: aFor modeling studies, this refers to the total sample size of the studies that the model data were estimated from, bOr less (i.e. until wound healed), c285 participants with 417 total wounds studied, dMost patients had surgical wounds (62% were postoperative wounds, 24% were from trauma, and 14% chronic wounds), *Denotes from a higher quality CEA/CUA. Abbreviations: CEA cost-effectiveness analysis, d days, IV intravenous, max maximum, NR not reported, US United States.


Table 16: Cost-effectiveness/cost-utility analyses results for diabetic ulcers (N=9)

Interventions

Study (study type,

country, currency, year of values,

perspective, sample sizea,

duration/ horizon)

Comparators Conclusion Standard

care Standard dressings

(gentamicin solution,

streptodornase/streptokinase, or dry saline gauze)

Non-adherent, knitted, viscose filament

gauze (N-A)

Total contact casting (TCC;

standard off-loading device)

Piperacillin/ Tazobactam

Placebo, (plus combination of

4 IV antibiotics: ceftazidime, amoxicillin,

flucloxacillin and metronidazole)

Hyperbaric oxygen therapy (HBOT) plus standard care

Chuck et al. (CUA/CEA, Canada, CAN$, 2004, healthcare system, 305, 12 years)

Intervention saved CAN$9,091 compared to standard care alone (over 12 years)

Intervention was more effective & less costly than the comparator*

Guo et al. (CUA/CEA, US, US$, 2001, society, 126, 12 yearsc)

ICERs at years 1, 5, and 12 were: US$27,310, US$5,166 & US$2,255 per QALY gained, respectivelyd

Intervention was more effective yet more costly than standard care alone. Intervention was more cost-effective† in the longer-term (more than 1 year).

Cadexomer iodine ointment (Iodosorb)

Apelqvist&RagnarsonTennvall (CEA, Sweden, SEK, 1993, society, 41, 12 weeksb)

Intervention saved SEK418 per week compared to standard dressings

Intervention had similar effectiveness & was less costly compared to Comparator

Intensified treatment in a specialized

Habacher et al. (CEA, Austria, €, 2001, society, 86e,

Intervention group had fewer

Intervention was more effective & less


Interventions

Study (study type,



duration/ horizon)






gauze (N-A)







outpatient hospital department

15 yearsc) amputations and longer life expectancy

costly than standard care

Intervention A: A hydrocolloid dressing (Aquacel) Intervention B: A modern iodine antiseptic (Inadine)

Jeffcoate et al. (CUA/CEA, UK, £, 2007, healthcare system, 317, 24 weeks)

Intervention A (hydrocolloid) was the most costly. Nearly 70% of the dressing changes were undertaken by non-professionals in this study

All 3 groups had similar effectiveness. Intervention A (hydrocolloid) was the most costly. Comparator (non-adherent gauze) was the least costly.

Becaplermin gel (Regranex), containing recombinant human platelet derived growth factor, plus standard care

Persson et al. (CEA, Sweden, US$, 1999, NR, 194, 12 monthsf)

Intervention had 42% of patients with healed ulcer versus 30% with Comparator (20-week healing rate)

Intervention was more effective & less costly than good wound care alone*

Optima Diab walker (non-removeable off-loading device; off-the-shelf "instant"

Piaggesi et al. (CEA, Italy, €, NRg, NR, 40, 12 weeks)

Intervention reduced cost of treatment by 78% compared to

Intervention had similar effectiveness & was less costly compared to


Interventions

Study (study type,



duration/ horizon)






gauze (N-A)







TCC) Comparator standard total contact casting

Diabetic Foot Infections: Ertapenem

Jansen et al. (CUA/CEA, UK, £, 2006, healthcare system, 402, 1 monthh)

The model’s (estimated) results found that any difference in AMR over time with the 2 groups will likely result in increasing CE favouring Ertapenem.

Intervention was more effective & less costly than Comparator*

Filgrastim, (plus combination of 4 IV antibiotics: ceftazidime, amoxicillin, flucloxacillin and metronidazole)

Edmonds et al. (CEA, UK, £, 1996, provider, 40, range 7-15 days)

Intervention saved £2666 (36%) compared to Comparator

Intervention was more effective & less costly than placebo (plus antibiotics)

Notes:aFor modeling studies, this refers to the total sample size of the studies that the model data were estimated from, bOr until stoppedexudating, at which time vaseline gauze was used, cOr less (i.e. until wound healed or amputation), dThere were an average of 29 HBOT treatments, e86 participants with 119 total wounds studied, fExtrapolated from treatment duration of up to 5 months (which was the limit of indicated use), gTrial conducted in 2005; publication date 2007, hOr less (i.e. until infection cured or treatment failure). Average was 11 days treatment, *Denotes from a higher quality CEA/CUA, †Using a conservative cost-effectiveness “threshold” of ≤$20,000 per QALY gained. Abbreviations: AMRantimicrobial resistance, CAN Canadian, CE cost-effectiveness, CEA cost-effectiveness analysis, CUA cost-utility analysis, HBOT hyperbaric oxygen therapy, ICER incremental cost-effectiveness ratio, IV intravenous, NR not reported, QALY quality-adjusted life year, SEK Swedish Krona, TCC total contact casting, UK United Kingdom, US United States.


Table 17: Cost-effectiveness/cost-utility analyses results for mixed acute and/or chronic ulcers (N=2)

Interventions Study (study type,



duration/ horizon)

Comparators Conclusion Standard care Hybrid nursing care modelb

Chronic Non-Healing Wounds (11 venous, 9 pressure, & 1 trauma): Bio-electric stimulation therapy (Posifect)

Clegg & Guest (CUA/ CEA, UK, £, 2005/2006, healthcare system, 18, 16 weeks)

Intervention group had 33% of wounds healed versus Comparator (previous standard care) which had none healed for at least the past 6 months

Intervention was more effective & less costly than patients’ previous standard care

Chronic & Acute Wounds (360 various chronic wounds & 54 acute surgical wounds): Specialty ET/AWOS nursing agency onlyc

Harris & Shannon (CEA, Canada, CAN$, 2005, NR, 414, until DC from homecare)

For chronic wounds: Intervention group healed 45 days faster than Comparator group

For chronic wounds: Intervention was more effective & less costly than Hybrid nursing care model. For acute wounds: within the Hybrid model, over 50% involvement by ET/AWOS was more cost-effective compared to less than 50% involvement by ET/AWOS.

Notes:aFor modeling studies, this refers to the total sample size of the studies that the model data were estimated from, bSpecialty ET nursing agency (i.e. with ET nurses and RNs with AWOS) coordinated visits with RN and RPN visiting nurses from other community nursing agencies, cPatients were seen exclusively by the specialty agency. Abbreviations: AWOS advanced wound and ostomy skills, CAN Canadian, CEA cost-effectiveness analysis, CUA cost-utility analysis, DC discharged, ET enterostomal, NR not reported, RN registered nurse, RPN registered practical nurse, UK United Kingdom.


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64. O'Brien JF, Grace PA, Perry IJ, Burke PE, EA. N: 4 layer bandaging reduced healing

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65. Oien RF, Hakansson A, Ahnlide I, Bjellerup M, Hansen BU, Borgquist L: Pinch

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66. Augustin M, Siegel A, Heuser A, W. V: Chronic leg ulcers: Cost evaluation of two

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67. Guest JF, Taylor RR, Vowden K, Vowden P: Relative cost-effectiveness of a skin

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68. Morrell CJ, Walters SJ, Dixon S, Collins KA, Brereton LM, Peters J, et al: Cost

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70. Gordon L, Edwards H, Courtney M, Finlayson K, Shuter P, Lindsay E: A cost-

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71. Colwell JC, Foreman MD, Trotter JP: A comparison of the efficacy and cost-

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73. Muller E, van Leen MW, Bergemann R: Economic evaluation of collagenase-

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77. Graumlich JF, Blough LS, McLaughlin RG, Milbrandt JC, Calderon CL, Agha SA, et al:

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78. Apelqvist J, Armstrong DG, Lavery LA, Boulton AJ: Resource utilization and

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79. Patanwala AE, Erstad BL, Nix DE: Cost-effectiveness of linezolid and vancomycin in

the treatment of surgical site infections. Current medical research and opinion 2007,

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80. Ubbink DT, Vermeulen H, Goossens A, Kelner RB, Schreuder SM, Lubbers MJ:

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82. Guo S, Counte MA, Gillespie KN, Schmitz H: Cost-effectiveness of adjunctive

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83. Habacher W, Rakovac I, Gorzer E, Haas W, Gfrerer RJ, Wach P, et al: A model to

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85. Apelqvist J, Ragnarson Tennvall G: Cavity foot ulcers in diabetic patients: a

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86. Piaggesi A, Macchiarini S, Rizzo L, Palumbo F, Tedeschi A, Nobili LA, et al: An off-

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87. Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al: Randomised

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88. Jansen JP, Kumar R, Carmeli Y: Accounting for the development of antibacterial

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90. Clegg JP, Guest JF: Modelling the cost-utility of bio-electric stimulation therapy

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91. Harris C, Shannon R: An innovative enterostomal therapy nurse model of community

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93. Black WC: The CE plane: a graphic representation of cost-effectiveness. Medical

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95. Jull A, Walker N, Parag V, Molan P, Rodgers A, Honey as Adjuvant Leg Ulcer Therapy

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96. Michaels JA, Campbell WB, King BM, Macintyre J, Palfreyman SJ, Shackley P, et al: A

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97. Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al: VenUS II:

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98. Medical Advisory Secretariat: Hyperbaric oxygen therapy for non-healing ulcers in

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99. Medical Advisory Secretariat: Community-based care for chronic wound

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103. Xie X, McGregor M, Dendukuri N: The clinical effectiveness of negative pressure

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bandaging for venous ulcers. The British journal of surgery 2003, 90:794-798.


Appendix 1: Description of interventions

Apligraf – type of artificial skin graft consisting of a dermal layer of human fibroblasts in type 1 bovine collagen with an epidermal layer formed by human keratinocytes

Autologous platelet rich plasma – blood plasma obtained from a blood sample from the patient containing fibrin and high concentrations of growth factors

Cryopreserved allografts – frozen bioengineered skin grown from donor cells

Dermagraft – type of artificial skin graft consisting of a dermal layer of human neonatal fibroblasts

Granulocyte-macrophage colony-stimulating factor (GM-CSF)–type of topical cream that binds to stem cells and most myelocytes, stimulating wound healing

Intermittent pneumatic compression – medical device that applies compression treatment to the wound by expanding with air

Micronized purified flavonoid - edema-protective agent consisting of 90%diosmin and 10% flavonoids expressed as hesperidin

Recombinant human platelet-derived growth factor – B chain dimeric protein available as a sodium carboxymethycellulose-based gel that promotes the growth of tissue at the wound site using recombinant DNA technology

Topical negative pressure (TNP) – medical devices that can be used to apply localized negative pressure to the wound

Unna’s boot – type of paste bandageimpregnated with glycerine, calamine lotion, and zinc oxide

Vacuum assisted closure (VAC) – type of medical device that applies controlled, localized negative pressure to the wound


Appendix 2: Scoping review approach

Note:The scoping review entails all steps until the meta-analysis.


Appendix 3: Search strategy for the MEDLINE database

1 Pressure Ulcer/ [ Wound terms ]

2 (pressureadj ulcer$).tw.

3 (pressureadj sore$).tw.

4 (decubitusadj ulcer$).tw.

5 (decubitusadj sore$).tw.

6 (bedadj ulcer$).tw.

7 (bedadj sore$).tw.

8 Surgical Wound Infection/

9 Surgical Wound Dehiscence/

10 (surg$ adj2 wound$).tw.

11 (surg$ adj infect$).tw.

12 (surg$ adj2 dehiscence).tw.

13 (arterial adj2 ulcer$).tw.

14 (ischemicadj ulcer$).tw.

15 (neuropathicadj ulcer$).tw.

16 (vascul$ adj ulcer$).tw.

17 Varicose Ulcer/

18 (varicoseadj ulcer$).tw.

19 (venous adj2 ulcer$).tw.

20 (stasisadj ulcer$).tw.

21 Skin Ulcer/

22 exp Foot Ulcer/


23 (footadj ulcer$).tw.

24 Leg Ulcer/

25 (legadj ulcer$).tw.

26 (diabeticadj foot).tw.

27 (diabeticadj feet).tw.

28 (cruraladj ulcer$).tw.

29 (ulcusadjcruris).tw.

30 (chronicadj wound$).tw.

31 (chronicadj sore$).tw.

32 (chronicadj ulcer$).tw.

33 or/1-32

34 exp Adult/ [ adult search filter - validated ]

35 adult.mp.

36 Middle Aged/

37 age$.tw.

38 or/34-37

39 meta analysis.mp,pt. [ systematic review filter - validated ]

40 review.pt.

41 search$.tw.

42 or/39-41 (1912330)

43 cost$.mp. [ economics filter - validated ]

44 cost benefit analys$.mp.

45 health care costs.mp.


46 or/43-45

47 42 or 46

48 33 and 38 and 47

49 exp Animals/ not (exp Animals/ and Humans/)

50 48 not 49


Appendix 4: Screening criteria for titles and abstracts (level 1 screening)

Question 1

This report is a a.systematic review/economic protocol b.conference abstract c. letter to the editor without data d.non-English article

Question 2

Is this a systematic review (according to the Cochrane Collaboration definition) or a health economics study?

Systematic review - A review of a clearly formulated question that uses systematic and explicit methods to identify (e.g. search multiple databases), select (e.g. screen for inclusion), collect and critically appraise relevant research. Statistical methods (e.g. meta-analysis) may or may not be used to analyse and summarize the results of the included studies [The Cochrane Handbook – www.cochrane-handbook.org].

Note:Quality appraisal or statistical analysis is not necessary for inclusion; however, reportMUSTbea review or synthesis of evidence AND include a description of the methods. Health Economics– include all economic analyses comparing the relationship between costs and outcomes of healthcare interventions. Examples include cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis. We will also include costing studies.

Note: Only include study if there is a focus on cost. Exclude case-series, case reports or studies that do not have an adequate comparison group.

Costing study – examines costing data associated with providing an intervention

Cost-benefit analysis – converts effects into the same monetary terms as costs and compares them

Cost-effectiveness analysis – views effects in terms of overall health specific to the problem, and describes the costs for some additional health gain (e.g. cost per additional stroke prevented)

Cost-utility analysis – expresses effects as overall health improvement and describes how much it costs for some additional utility gain (e.g. cost per additional quality-adjusted life-year)

Definitions from the Cochrane Collaboration Glossary at http://www.cochrane.org/glossary/5#letterc Note:For citations with NO ABSTRACTS, there must be some indication in the title that the report is a systematic review or costing study AND is related to wound care to be included.

Please indicate if the report fulfills the study eligibility criteria BUT is a study protocol (i.e. from Cochrane, PROSPERO, registries), a conference proceeding/abstract, a letter to the editor or a non-English article. Note: If none of the above, please leave unanswered.

http://www.cochrane.org/glossary/5#term292�

http://www.cochrane-handbook.org/�

http://www.cochrane.org/glossary/5#letterc�


Question 3

Does the report include adult patients in need of wound care?

Note:This is a mandatory question.

Adult patients – aged 16 years and older.Note: Exclude studies ONLY looking at children or animals.

Patients in need of wound care – including those with pressure ulcers (e.g. decubitus ulcers, bed sores), post-surgical wounds (e.g. incisions, surgical dehiscence, surgical infections), wounds due tochronic disease (e.g. arterial and venous ulcers, diabetic foot, pyodermagangrenosum) and non-superficial burns (e.g. deep dermal burn, burn infections).

Note: We will include patients with a variety of wounds, sores, ulcers and/or burns; however we will exclude superficial burns, anal fissures, and hemorrhoids). Question 4

Does this report examine an intervention or a care program to treat wounds?

We are EXCLUDING diagnosing wounds, preventing wounds, assessing wounds, prognosis of wounds, epidemiology of wounds, incidence of wounds, prevalence of wounds, and frequency of wounds. Instead, we are focusing on the management and treatment of wounds.

Note: If report is a review or costing study of both prevention AND treatment, we will include.

Potential interventions include: Pharmacological agents - e.g. topical agents.

Non-pharmacological agents - e.g. dressing, vacuum, honey, hyperbaric therapy. Wound care programs – e.g. care management, self-management or other quality improvement interventions (see box below).

Case management - is a QI strategy involving coordinating diagnosis, treatment, or ongoing patient management (e.g., arrangement for referrals, follow-up of test results) by a person or multi-disciplinary team in collaboration with or supplementary to the primary care clinician. In order for a trial to qualify as case management, it has to be ongoing (i.e. occur more than once). Usually these studies involved less involvement compared with team changes (i.e. case manager does not have to speak with primary care physician). If the study called the intervention “case management” we will classify it as such.

Team changes - is a QI strategy involving changes to the structure or organization of the primary health care team, defined as present if any of the following applied:

• Adding a team member or “shared care,” i.e. routine visits with personnel other than the primary physician (including physician or nurse specialists in diabetic care, pharmacists, nutritionists, podiatrists).

• Use of multidisciplinary teams, i.e. active participation of professionals from more


than 1 discipline (i.e. medicine, nursing, pharmacy, nutrition) in the primary, ongoing management of patients.

• Expansion or revision of professional roles (e.g., nurse or pharmacist plays more active role in patient monitoring or adjusting medication regimens).

In order to ensure that not every study classified as case management will also qualify as a team change, if the study was already classified as case management, it could also be a team change if at least two of the above conditions were met. Team changes generally involve more communication. If the study calls the intervention “joint visits” or “shared care”, we will classify it as a team change. To qualify, the intervention had to be done by a health-care professional and had to happen more than once.

Promotion of Self-management – is a QI strategy involving provision of equipment (e.g., home glucometers) or access to resources (e.g., system for electronically transmitting home glucose measurements and receiving insulin dose changes based on those data) to promote self-management. We will also include established goals or a print off of a self-management plan (i.e. didn’t necessarily require equipment or resources). This was generally considered a more active strategy than patient education. If the study calls the intervention promotion of self-management, personalized goal-setting or action-planning then we will include it here.

Decision support – is a QI strategy which occurs as an operational process of adjustment in the case of a system that generates regular feedback for clinical teams on guideline compliance from registry data, or simply an organizational support to help facilitate other coordination mechanisms.

Clinical information system – is a QI strategy encompassing systems performing a wide variety of functions. A general feature that serves to distinguish clinical information systems from administrative information systems is that the former require data entry or data retrieval by clinicians at the point of care.

Patient education – is a QI strategy designed to promote increased understanding of a target condition or to teach specific prevention or treatment strategies, or specific in-person patient education (e.g., individual or group sessions with diabetes nurse educator; distribution of printed or electronic educational materials). If the patient education is optional, it will be excluded.

Patient reminder systems – is a QI strategy involving any effort (e.g., postcards or telephone calls) to remind patients about upcoming appointments or important aspects of self-care. Examples include reminders to monitor glucose. If the intervention included case management, reminders to patients needed to be explicit and an extra task to the normal case management.

Clinician education – is a QI strategy designed to promote increased understanding of principles guiding clinical care or awareness of specific recommendations for a target disorder or population of patients. Subcategories of clinician education included conferences or workshops, distribution of educational materials (written, video, or


other), and educational outreach visits (i.e. academic detailing). Exclude: teaching how to educate patients, counseling skills, motivational interviewing, self-directed learning, and skills related to the intervention (i.e. teaching how to use the website for the randomized clinical trial). If the education was part of the individual’s role (i.e. teaching a case manager about diabetes) we will NOT categorize it as clinician education.

Clinician reminders – is a QI strategy involving paper-based or electronic systems intended to prompt a health professional to recall patient-specific information or to do a specific task. An example is a yellow piece of paper clipped to the medical record with the patient’s information on it. This approach had to be systematic and part of the implementation of the intervention—ad-hoc clinician reminders will be excluded.

Audit and feedback – is a QI strategy involving a summary of clinical performance of health care delivered by an individual clinician or clinic over a specified period, which was then transmitted back to the clinician (i.e. the percentage of a clinician’s patients who achieved a target HbA1c concentration or who underwent dilated-eye examinations with a specified frequency). It could also include the number of patients with missing tests and dropouts. This strategy is strictly based on clinical data and excludes clinical skills.

Financial incentives - is a QI strategy encompassing interventions with positive or negative financial incentives directed at providers (i.e. linked to adherence to some process of care or achievement of some target outcome). This strategy also includes positive or negative financial incentives directed at patients or system-wide changes in reimbursement (i.e. capitation, prospective payment, or a shift from fee-for-service to salary pay structure).

Continuous QI - is a QI strategy involving interventions explicitly identified as involving the techniques of continuous QI, total quality management, or plan-do-study-act, or any iterative process for assessing quality problems, developing solutions to those problems, testing their effects and then reassessing the need for further action.

Facilitated relay of information to clinicians – Clinical information collected from patients and transmitted to clinicians by means other than the existing medical record. We will exclude conventional means of correspondence between clinicians. For example, if the results of routine visits with a pharmacist were sent in a letter to the primary-care physician, the use of routine visits with a pharmacist would count as a “team change”, but the intervention would not also be counted as “facilitated relay”. However, if the pharmacist issued structured diaries for patients to record self-monitored glucose values, which were then taken to office visits to review with the primary physician, we would count the intervention as “facilitated relay”. Other examples include electronic web-based methods through which patients provided self-care data and which clinicians reviewed, as well as point-of-care testing supplying clinicians with immediate HbA1c values. We will include passports, referral systems, and dietary information (versus purely clinical information). In general, the patient should be facilitating the relay. To be included, the information must get to someone


with prescribing or ordering ability. For example, if the nurse’s role was expanded to make drug changes, the patient had a passport, and the nurse could directly make a change, we would classify the intervention as case management and facilitated relay of clinical information. If the nurse alerted the primary-care provider that the patient had run out of drugs, we did not deem this facilitated relay of information, because that is a normal part of a nurse’s role.

Adapted from: Tricco AC, Ivers NM, Grimshaw JM, Moher D, Turner L, Galipeau J, Halperin I, Vachon B, Ramsay T, Manns B, Tonelli M, Shojania K. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. Lancet. 2012 Jun 16;379(9833):2252-61.


Appendix 5: Screening criteria for full-text articles (level 2 screening)

Question 1

This report is a e. study protocol f. conference abstract g.letter to the editor without data h.non-English article

Question 2

Is this a systematic review (according to the Cochrane Collaboration definition) or a health economics study?

Systematic review - A review of a clearly formulated question that uses systematic and explicit methods to identify (e.g. search multiple databases), select (e.g. screen for inclusion), collect and critically appraise relevant research. Statistical methods (e.g. meta-analysis) may or may not be used to analyse and summarize the results of the included studies [The Cochrane Handbook – www.cochrane-handbook.org].

Note:Quality appraisal or statistical analysis is not necessary for inclusion; however, reportMUSTbea review or synthesis of evidence AND include a description of the methods. Health Economics– include all economic analyses comparing the relationship between costs and outcomes of healthcare interventions. Examples include cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis. We will also include costing studies.

Note: Only include study if there is a focus on cost. Exclude case-series, case reports or studies that do not have an adequate comparison group.

Costing study – examines costing data associated with providing an intervention

Cost-benefit analysis – converts effects into the same monetary terms as costs and compares them

Cost-effectiveness analysis – views effects in terms of overall health specific to the problem, and describes the costs for some additional health gain (e.g. cost per additional stroke prevented)

Cost-utility analysis – expresses effects as overall health improvement and describes how much it costs for some additional utility gain (e.g. cost per additional quality-adjusted life-year)

Definitions from the Cochrane Collaboration Glossary at http://www.cochrane.org/glossary/5#letterc

Note:For citations with NO ABSTRACTS, there must be some indication in the title that the report is a systematic review or costing study AND is related to wound care to be included. Question 3

Please indicate if the report fulfills the study eligibility criteria BUT is a study protocol (i.e. from Cochrane, PROSPERO, registries), a conference proceeding/abstract, a letter to the editor or a non-English article. Note:If none of the above, please leave unanswered.

http://www.cochrane.org/glossary/5#term292�

http://www.cochrane-handbook.org/�

http://www.cochrane.org/glossary/5#letterc�


If you selected YES or UNSURE to Question 2, please check all that apply from the following:

This is a systematic review This is a health economics study

Question 4

Does the report include adult patients in need of wound care?

Note:This is a mandatory question.

Adult patients – aged 16 years and older.Note: Exclude studies ONLY looking at children or animals.

Patients in need of wound care – including those withexistingpressure ulcers (e.g. decubitus ulcers, bed sores),post-surgical wounds (e.g. incisions, surgical dehiscence, surgical infections), wounds due to chronic disease (e.g. arterial and venous ulcers, diabetic foot, pyodermagangrenosum) and non-superficial burns (e.g. deep dermal burn, burn infections).

Note: We will include patients with a variety of wounds, sores, ulcers and/or burns; however we will exclude superficial burns, anal fissures, and hemorrhoids).

Question 5

Does this report examine an intervention or a care program to treat wounds?

We are EXCLUDING diagnosing wounds, preventing wounds/infections, assessing wounds, prognosis of wounds, epidemiology of wounds, incidence of wounds, prevalence of wounds, and frequency of wounds. Instead, we are focusing on the management and treatment of wounds.

Note: If report is a review or costing study of both prevention AND treatment, we will include.

Potential interventions - pharmacological agents (e.g. topical agents), non-pharmacological agents(e.g. dressing, vacuum, honey, hyperbaric therapy), wound care programs (e.g. care management, self-management or other quality improvement interventions found in box below).

Question 6

Does this report examine any of the following outcomes: healing, recovery, admission/readmission to hospital, human resources, or cost?

Outcomes of interest - healing/recovery (e.g. time to heal, duration of recovery, extent of healing), admission/readmission to hospital (as a result of the wound), human resources (necessary staff required to deliver/implement treatment) and cost (e.g. cost-effectiveness, cost-benefit, cost-utility, costing data).

Quality Improvement Strategies

Indicate whether the report is a systematic review, health economics study or both by checking the appropriate boxes.

Note:Ifyou selected NO to Question 2, please leave unanswered.


Case management - is a QI strategy involving coordinating diagnosis, treatment, or ongoing patient management (e.g., arrangement for referrals, follow-up of test results) by a person or multi-disciplinary team in collaboration with or supplementary to the primary care clinician. In order for a trial to qualify as case management, it has to be ongoing (i.e. occur more than once). Usually these studies involved less involvement compared with team changes (i.e. case manager does not have to speak with primary care physician). If the study called the intervention “case management” we will classify it as such.

Team changes - is a QI strategy involving changes to the structure or organization of the primary health care team, defined as present if any of the following applied:

• Adding a team member or “shared care,” i.e. routine visits with personnel other than the primary physician (including physician or nurse specialists in diabetic care, pharmacists, nutritionists, podiatrists).

• Use of multidisciplinary teams, i.e. active participation of professionals from more than 1 discipline (i.e. medicine, nursing, pharmacy, nutrition) in the primary, ongoing management of patients.

• Expansion or revision of professional roles (e.g., nurse or pharmacist plays more active role in patient monitoring or adjusting medication regimens).

In order to ensure that not every study classified as case management will also qualify as a team change, if the study was already classified as case management, it could also be a team change if at least two of the above conditions were met. Team changes generally involve more communication. If the study calls the intervention “joint visits” or “shared care”, we will classify it as a team change. To qualify, the intervention had to be done by a health-care professional and had to happen more than once.

Promotion of Self-management – is a QI strategy involving provision of equipment (e.g., home glucometers) or access to resources (e.g., system for electronically transmitting home glucose measurements and receiving insulin dose changes based on those data) to promote self-management. We will also include established goals or a print off of a self-management plan (i.e. didn’t necessarily require equipment or resources). This was generally considered a more active strategy than patient education. If the study calls the intervention promotion of self-management, personalized goal-setting or action-planning then we will include it here.

Decision support – is a QI strategy which occurs as an operational process of adjustment in the case of a system that generates regular feedback for clinical teams on guideline compliance from registry data, or simply an organizational support to help facilitate other coordination mechanisms.

Clinical information system – is a QI strategy encompassing systems performing a wide variety of functions. A general feature that serves to distinguish clinical information systems from administrative information systems is that the former require data entry or data retrieval by clinicians at the point of care.


Patient education – is a QI strategy designed to promote increased understanding of a target condition or to teach specific prevention or treatment strategies, or specific in-person patient education (e.g., individual or group sessions with diabetes nurse educator; distribution of printed or electronic educational materials). If the patient education is optional, it will be excluded.

Patient reminder systems – is a QI strategy involving any effort (e.g., postcards or telephone calls) to remind patients about upcoming appointments or important aspects of self-care. Examples include reminders to monitor glucose. If the intervention included case management, reminders to patients needed to be explicit and an extra task to the normal case management.

Clinician education – is a QI strategy designed to promote increased understanding of principles guiding clinical care or awareness of specific recommendations for a target disorder or population of patients. Subcategories of clinician education included conferences or workshops, distribution of educational materials (written, video, or other), and educational outreach visits (i.e. academic detailing). Exclude: teaching how to educate patients, counseling skills, motivational interviewing, self-directed learning, and skills related to the intervention (i.e. teaching how to use the website for the randomized clinical trial). If the education was part of the individual’s role (i.e. teaching a case manager about diabetes) we will NOT categorize it as clinician education.

Clinician reminders – is a QI strategy involving paper-based or electronic systems intended to prompt a health professional to recall patient-specific information or to do a specific task. An example is a yellow piece of paper clipped to the medical record with the patient’s information on it. This approach had to be systematic and part of the implementation of the intervention—ad-hoc clinician reminders will be excluded.

Audit and feedback – is a QI strategy involving a summary of clinical performance of health care delivered by an individual clinician or clinic over a specified period, which was then transmitted back to the clinician (i.e. the percentage of a clinician’s patients who achieved a target HbA1c concentration or who underwent dilated-eye examinations with a specified frequency). It could also include the number of patients with missing tests and dropouts. This strategy is strictly based on clinical data and excludes clinical skills.

Financial incentives - is a QI strategy encompassing interventions with positive or negative financial incentives directed at providers (i.e. linked to adherence to some process of care or achievement of some target outcome). This strategy also includes positive or negative financial incentives directed at patients or system-wide changes in reimbursement (i.e. capitation, prospective payment, or a shift from fee-for-service to salary pay structure).

Continuous QI - is a QI strategy involving interventions explicitly identified as involving the techniques of continuous QI, total quality management, or plan-do-study-


act, or any iterative process for assessing quality problems, developing solutions to those problems, testing their effects and then reassessing the need for further action.

Facilitated relay of information to clinicians – Clinical information collected from patients and transmitted to clinicians by means other than the existing medical record. We will exclude conventional means of correspondence between clinicians. For example, if the results of routine visits with a pharmacist were sent in a letter to the primary-care physician, the use of routine visits with a pharmacist would count as a “team change”, but the intervention would not also be counted as “facilitated relay”. However, if the pharmacist issued structured diaries for patients to record self-monitored glucose values, which were then taken to office visits to review with the primary physician, we would count the intervention as “facilitated relay”. Other examples include electronic web-based methods through which patients provided self-care data and which clinicians reviewed, as well as point-of-care testing supplying clinicians with immediate HbA1c values. We will include passports, referral systems, and dietary information (versus purely clinical information). In general, the patient should be facilitating the relay. To be included, the information must get to someone with prescribing or ordering ability. For example, if the nurse’s role was expanded to make drug changes, the patient had a passport, and the nurse could directly make a change, we would classify the intervention as case management and facilitated relay of clinical information. If the nurse alerted the primary-care provider that the patient had run out of drugs, we did not deem this facilitated relay of information, because that is a normal part of a nurse’s role.

Adapted from: Tricco AC, Ivers NM, Grimshaw JM, Moher D, Turner L, Galipeau J, Halperin I, Vachon B, Ramsay T, Manns B, Tonelli M, Shojania K. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. Lancet. 2012 Jun 16;379(9833):2252-61.


Appendix 6: Data abstraction form for systematic reviews

For all items, if not reported indicate by inserting ‘NR’. Please do not leave blank.

Review Characteristics ***Please abstract for ALL studies

Excel Column Description RefID Reference ID of review (5-digit file number) First Author Last name of first author listed on review Year Year of publication Country of conduct Name of country in which the review was conducted No. of studies Number of studies included in review Study design_RCT Does this review include randomized, quasi-randomized or cluster-

randomized clinical trials? Select YES, NO or UNCLEAR from list. Study design_NRCT Does this review include non-randomized clinical trials or controlled clinical

trials? Study design_CBA/ITS Does this review include controlled before-after or interrupted time series

studies? Study design_OBS Does this review include prospective or retrospective observational (cohort,

case-control, cross-sectional) studies? Wound type_1 Name the primary type of wound included in review (e.g. pressure ulcers,

post-surgical wounds, sores, etc). See Eligibility below. No. wound type_1 Number of studies in review including patients with wound type 1 Wound type_2 If more than one type of wound included, name second type here No. wound type_2 Number of studies in review including patients with wound type 2 Wound type_3 Name third type of wound included, if applicable No. wound type_3 Number of studies in review including patients with wound type 3 Age category Age range of included participants (i.e. 20-50, >65, etc) Patient population Describe patient population by giving main reason for wounds (e.g. diabetes,

chronic venous insufficiency, surgery, etc). Comorbidities 5 most prevalent comorbidities and conditions present in review participants

(e.g. diabetes, heart condition, smokers, etc) Wound txs Name all wound care interventions included in review (e.g. silver dressing,

vacuum, honey, case management). See Eligibility below. Controls Name all comparison groups included in review (e.g. no intervention, usual

care, other wound care intervention, etc) Care setting Where was the intervention(s) delivered (e.g. hospital, burn centre, wound

clinic, etc)? Length of tx_range Provide range (shortest – longest) of the intervention periods in weeks (e.g.

0-1 week, 1-3 weeks, 1-12 weeks, etc) Length of F/U_range Provide range (shortest – longest) of follow-up periods in weeks (e.g. 2-6

weeks, 0-12 weeks, etc). Abstract Results Textbox Copy and paste results section of review abstract. If no summary data

provided, please indicate by entering NSD.


Meta-analysis Outcomes***Use data from meta-analysis (MA) for these outcomes If multiple outcomes of interest analyzed, repeat steps below for all relevant meta-analyses (e.g. MA2, MA3, MA4, etc). Room to abstract up to 10 MAs.

Quality Appraisal using AMSTAR tool

Choose either ‘YES’, ‘NO’, ‘UNCLEAR’ or ‘NOT APPLICABLE’ for each of the following:

Excel Column Description Wound type_MA1 Name wound type(s) included in this meta-analysis. Wound tx_MA1 Name intervention analyzed in this MA. Wound control_MA1 Name comparison analyzed in this MA. Outcome_MA1 Name outcome analyzed in this MA. See Eligibility below. No. of studies_MA1 Number of studies included in this MA Authors and years_MA1 List the last names and years of publication of each of the studies included

in this meta-analysis (e.g. Rich 1994, McCorkle 200, etc). No. in tx_MA1 Total number of participants in intervention arm of MA No. in control_MA1 Total number of participants in comparison arm of MA No. overall_MA1 Overall number of participants in MA MA1_RR Relative risk of MA1 outcome MA1_RR95CI 95% confidence interval of MA1_RR MA1_OR Odds ratio of MA1 outcome MA1_OR95CI 95% confidence interval of MA1_OR MA1_MD Mean difference of MA1 outcome MA1_MD95CI 95% confidence interval of MA1_MD MA1 Outcomes Textbox Type in any other results from MA1 not captured above.

A priori design Was an 'a priori' design provided? The research question and inclusion criteria should be established before the conduct of the review. This means that the authors must mention that they worked from a protocol or that they registered their review protocol or that they published their review protocol. All Cochrane reviews will automatically have a YES here.

Duplicate selection/DA Was there duplicate study selection and data extraction? There should be at least two independent data extractors and a consensus procedure for disagreements should be in place. Since this item lumps 2 questions into 1, data can be screened in duplicate and data abstraction verified or vice versa.

Literature search Was a comprehensive literature search performed? The report must include years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the search strategy should be provided. All searches should be supplemented by consulting current contents, reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the references in the studies found.In order to score a YES, at least two electronic sources should be searched.


If AMSTAR Rating >7, then continue to abstract other Outcomes tab. If not, stop here.

Publication status Was the status of publication (i.e. grey literature) used as an inclusion criterion? The authors should state that they searched for reports regardless of their publication type. The authors should state whether or not they excluded any reports (from the systematic review), based on their publication status, language etc. In order to score a YES, they should search/review/include unpublished data.

List of studies Was a list of studies (included and excluded) provided? To score a YES, all included and excluded full-texts screened at L2 should be provided.

Study characteristics Were the characteristics of the included studies provided? To score a YES, in an aggregated form such as a table, data from the original studies should be provided on the participants, interventions and outcomes.

Quality assessed Was the scientific quality of the included studies assessed and documented? To score a YES, they must appraise risk of bias or methodological quality.

Quality used Was the scientific quality of the included studies used appropriately in formulating conclusions? The results of the methodological rigor and scientific quality should be considered in the analysis and the conclusions of the review, and explicitly stated in formulating recommendations. To score a YES, discussion should include mention of quality results/limitations. If quality/risk of bias was not assessed, then this is NA.

Methods appropriate Were the methods used to combine the findings of studies appropriate? For the pooled results, a test should be done to ensure the studies were combinable, to assess their homogeneity (i.e. Chi squared test for homogeneity, I2). If heterogeneity exists, a random effects model should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is it sensible to combine?). For reviews that do not conduct a meta-analysis, authors should provide a rationale for this (e.g., the results were too homogenous so the results were described narratively). To score a YES, a test of homogeneity should be conducted and/or rationale for pooling results discussed. Reviews that do not describe their synthesis process should be scored as a NO.

Publication bias assessed Was the likelihood of publication bias assessed? An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test). If a MA was not conducted, then to score a YES the possibility of publication bias should be at least mentioned in discussion section (e.g. didn’t include unpublished data).

Conflicts stated Was the conflict of interest stated? Potential sources of support should be clearly acknowledged in both the systematic review and the included studies. Score as a YES even if a conflict of interest exists but it is stated. This item is asking whether it was reported (not whether conflicts of interest exist).


Other Outcome Data ***ONLY report these outcomes if no AMSTAR score >7

No. of wounds healed_tx Number of wounds healed in intervention group No. of wounds healed_control Number of wounds healed in comparison group Mean wounds healed_tx Average number of wounds healed in intervention SD wounds healed_tx Standard deviation of mean wounds healed in intervention Mean wounds healed_control Average number of wounds healed in comparison SD wounds healed_control Standard deviation of mean wounds healed in comparison Wound Healed Textbox Enter any aggregate outcome information regarding wounds

healed not captured above. If no summary data provided, please indicate by entering NSD.

Rate of healing_tx Rate of healing or recovery in intervention group Rate of healing_control Rate of healing or recovery in comparison Healing time_tx (in days) Time for wounds to heal or recover (in days) in treatment Healing time_control Time for wounds to heal or recover (in days) in control Healing Time/Rate Textbox Enter any aggregate outcome information regarding

healing/recovery time or rate not captured above. If no summary data provided, please indicate by entering NSD.

No. of admissions_tx Number of admissions/readmissions to hospital directly related to wounds in treatment group

No. of admissions _control Number of admissions/readmissions related to wounds in control group

Mean admission_tx Average number of admissions in treatment SD admission_tx Standard deviation of mean admission_tx Mean admission_control Average number of admissions in comparison SD admission_control Standard deviation of mean admission_control No. of patients admitted_tx Number of patients admitted due to wounds in treatment No. of patients admitted _control Number of patients admitted in control group Admissions Textbox Enter any aggregate outcome information regarding

admissions/readmissions not captured above. If no summary data provided, please indicate by entering NSD.

LOS_tx Length of hospital stay (in days) in intervention group LOS_control Length of hospital stay (in days) in control group LOS Textbox Enter any aggregate outcome information related to length of stay

not captured above. If no summary data provided, please indicate by entering NSD.

Resources_tx Outcomes on resources needed to implement intervention (e.g. cost of personnel, etc)

Resources_control Outcomes on resources needed to implement control. Resource Textbox Enter any aggregate resource outcome information. If no

summary data provided, please indicate by entering NSD.


Appendix 7: Data abstraction form for economic studies

NB - For all items if not applicable/reported, enter NA or NR. Please do not leave blank spaces.

If an article does not meet the inclusion criteria, please mark as To Exclude and do not abstract it.

Please do not abstract protocols, conference abstracts or non-English publications.

Excel Column Description RefID Enter publication’s RefID number First author Enter last name of the first author Year of publication Enter year of publication Study design Choose the type of study design as reported in the publication from the

following 7 drop-down menu options: CEA (cost-effectiveness analysis), CUA (cost- utility analysis), RCT (randomized controlled trial), Other exp’l study (use this for other experimental study designs), Quasi-exp’l study (i.e. CBA and TSA studies), Observat’l study (observational studies), Unclear (use this if the study design is not clearly reported).

Country of conduct Name of country in which the study was conducted Setting Where was the intervention delivered? (e.g., hospital, wound clinic, burn

centre, primary care, tertiary care, research institution, etc.). If not applicable, enter NA

Currency Enter currency used in the publication Perspective For economic evaluations, enter the point of view from which the costs and

benefits are assessed (i.e. patient, provider, payer, health care system, societal). See definitions below. If not applicable, enter NA

Model type For CEAs/CUAs, enter the type of model/framework used. If not applicable, enter NA

Funding Choose funding source from the following 4 drop-down menu options: public, private, mixed (both public and private), NR.

Year of values Enter year costs were calculated for Time horizon/Length of study period

Enter the number of years used in the economic model, or the length of the study treatment period

Sample size – participants/cohort

For single studies, enter the total number of study participants (enrolled). For models, enter the total number of study participants (combined if multiple studies used) that are used for the model estimations/extrapolations. If not applicable, enter NA.

Sample size – wounds For single studies, enter the total number of wounds studied. If not applicable, enter NA


Type of wounds Brief description of the type of wounds Population Brief description of the population. If not applicable, enter NA Comorbidities Enter the 5 most prevalent comorbidities reported of the sample population.

If not applicable, enter NA Intervention #1 information

In the relevant marked columns, list separately the following details for the intervention (#1): Name, Dose, Duration, Frequency, Administration, and/or Program/protocol details. For any of these columns, if it is not applicable, enter NA

Intervention(s) # 2-10 information

In the relevant marked columns, list separately the following details for the next intervention(s), if applicable (#s 2-10): Name, Dose, Duration, Frequency, Administration, and/or Program/protocol details. For any of these columns, if it is not applicable, enter NA

Comparator information

In the relevant marked columns, list separately the following details for the comparator (e.g., active control, standard care): Name, Dose, Duration, Frequency, Administration, and/or Program/protocol details. For any of these columns, if it is not applicable, enter NA

Total cost results -for Tx #1

Enter the total cost findings (as reported in the publication) for the intervention (#1), and the conclusion. If not applicable, enter NA

Total cost variation - for Tx #1

Enter the variation of the total cost for the intervention (#1), i.e. standard deviation (SD), standard error (SE), 95% confidence interval (CI), range or interquartile range (IQR) reported. If not reported, enter NR

Intervention cost - for Tx 1

Enter the (direct) intervention cost for the intervention (#1). If not reported, enter NR

Intervention cost variation - for Tx #1

Enter the variation of the (direct) intervention cost for the intervention (#1), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Personnel cost - for Tx Enter the personnel costs results for the intervention (#1). If not applicable,


1 enter NA Personnel cost variation - for Tx #1

Enter the variation of the personnel cost for the intervention (#1), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Hospital cost - for Tx 1 Enter the hospital costs results for the intervention (#1). If not applicable, enter NA

Hospital cost variation - for Tx #1

Enter the variation of the hospital cost for the intervention (#1), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Total cost results -for Tx(s) # 2-10

Enter the total cost findings for intervention(s) # 2-10 (if applicable), and the conclusion. If not applicable, enter NA

Total cost variation - for Tx(s) # 2-10

Enter the variation of the total cost for intervention(s) # 2-10 (if applicable), i.e. standard deviation (SD), standard error (SE), 95% confidence interval (CI), range or interquartile range (IQR) reported. If not reported, enter NR

Intervention cost - for Tx(s) # 2-10

Enter the (direct) intervention cost for intervention(s) # 2-10 (if applicable). If not reported, enter NR

Intervention cost variation - for Tx(s) # 2-10

Enter the variation of the (direct) intervention cost for intervention(s) # 2-10 (if applicable), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Personnel cost - for Tx(s) # 2-10

Enter the personnel costs results for intervention(s) # 2-10 (if applicable). If not applicable, enter NA

Personnel cost variation - for Tx(s) # 2-10

Enter the variation of the personnel cost for intervention(s) # 2-10 (if applicable), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Hospital cost - for Tx(s) # 2-10

Enter the hospital costs results for intervention(s) # 2-10 (if applicable). If not applicable, enter NA

Hospital cost variation - for Tx(s) # 2-10

Enter the variation of the hospital cost for intervention(s) # 2-10 (if applicable), i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Total cost results -for Comparator

Enter the total cost findings (as reported in the publication) for the comparator, and the conclusion. If not applicable, enter NA

Total cost variation - for Comparator

Enter the variation of the total cost for the comparator, i.e. standard deviation (SD), standard error (SE), 95% confidence interval (CI), range or interquartile range (IQR) reported. If not reported, enter NR

Intervention cost - for Comparator

Enter the (direct) intervention cost for the comparator. If not reported, enter NR

Intervention cost variation - for Comparator

Enter the variation of the (direct) intervention cost for the comparator, i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Personnel cost - for Comparator

Enter the personnel costs results for the comparator. If not applicable, enter NA

Personnel cost variation - for

Enter the variation of the personnel cost for the comparator, i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR


Study and Patient Characteristics:Outcomes of CEAs/CUAs:

Comparator Hospital cost - for Comparator

Enter the hospital costs results for the comparator. If not applicable, enter NA

Hospital cost variation - for Comparator

Enter the variation of the hospital cost for the comparator, i.e. SD, SE, 95% CI, range or IQR. If not reported, enter NR

Excel Column Description Relative/ Incremental costs results

For CEAs/CUAs, enter the relative/incremental costs results comparing the groups along with relevant explanatory textwords (e.g., ICER; whether the difference between groups was statistically significant; % savings from using tx 1 versus comparator, etc.). If not applicable, enter NA.

CEA/CUA cost results (#1): cost per LY

For CEAs/CUAs, enter the cost per life-year for intervention #1. If not applicable, enter NA

CEA/CUA costs (#1): cost per QALY

For CEAs/CUAs, enter the cost per quality-adjusted life-year for intervention #1. If not applicable, enter NA

CEA/CUA costs (#1): cost per wound healed

For CEAs/CUAs, enter the cost per ulcer/wound healed/improved for intervention #1, along with relevant text details (e.g., “per wound infection resolved”, etc.). If not applicable, enter NA

CEA/CUA cost results (#1): other indicator costs

For CEAs/CUAs, enter costs reported for other indicator types (i.e. other than LY/QALY) for intervention #1. If not applicable, enter NA

Sensitivity analyses (#1) - for CEA/CUA

For CEAs/CUAs, enter (only) the key model parameters that were found to be sensitive in the sensitivity analysis for intervention #1. List up to 5 sensitive parameters. If none were significant, enter Nil. If not reported, enter NR.

CEA/CUA cost results (#s 2-10): cost per LY

For CEAs/CUAs, enter the cost per life-year for intervention(s) # 2-10 (if applicable). If not applicable, enter NA

CEA/CUA costs (#s 2-10): cost per QALY

For CEAs/CUAs, enter the cost per quality-adjusted life-year for intervention(s) # 2-10 (if applicable). If not applicable, enter NA

CEA/CUA costs (#s 2-10): cost per wound healed

For CEAs/CUAs, enter the cost per ulcer/wound healed/improved for intervention(s) # 2-10 (if applicable), along with relevant text details (e.g., “per wound infection resolved”, etc.). If not applicable, enter NA

CEA/CUA cost results For CEAs/CUAs, enter costs reported for other indicator types (i.e. other than


Quality Assessment* of CEAs/CUAs:

(#s 2-10): other indicator costs

LY/QALY) for intervention(s) # 2-10 (if applicable). If not applicable, enter NA

Sensitivity analyses (#s 2-10) – for CEA/CUA

For CEAs/CUAs, enter (only) the key model parameters that were found to be sensitive in the sensitivity analysis for intervention(s) # 2-10 (if applicable). List up to 5 sensitive parameters. If none were significant, enter Nil. If not reported, enter NR.

CEA/CUA cost results (Comparator): cost per LY

For CEAs/CUAs, enter the cost per life-year for the comparator. If not applicable, enter NA

CEA/CUA costs (Comparator): cost per QALY

For CEAs/CUAs, enter the cost per quality-adjusted life-year for the comparator. If not applicable, enter NA

CEA/CUA costs (Comparator): cost per wound healed

For CEAs/CUAs, enter the cost per ulcer/wound healed/improved for the comparator, along with relevant text details (e.g., “per wound infection resolved”, etc.). If not applicable, enter NA

CEA/CUA cost results (Comparator): other indicator costs

For CEAs/CUAs, enter costs reported for other indicator types (i.e. other than LY/QALY) for the comparator. If not applicable, enter NA

Sensitivity analyses (Comparator) - for CEA/CUA

For CEAs/CUAs, enter (only) the key model parameters that were found to be sensitive in the sensitivity analysis for the comparator. List up to 5 sensitive parameters. If none were significant, enter Nil. If not reported, enter NR.

Excel Column Description Q1. Was a well-defined question posed in answerable form?

1.1. Did the study examine both costs and effects of the service(s) or programme(s)? 1.2. Did the study involve a comparison of alternatives? 1.3. Was a viewpoint for the analysis stated and was the study placed in any particular decision-making context?

Q2. Was a comprehensive description of the competing alternatives given (i.e. can you tell who did what to whom, where, and how often)?

2.1. Were any relevant alternatives omitted? 2.2. Was (should) a do-nothing alternative (be) considered?


Q3. Was the effectiveness of the programme or services established?

3.1. Was this done through a randomised, controlled clinical trial? If so, did the trial protocol reflect what would happen in regular practice? 3.2. Were effectiveness data collected and summarized through a systematic overview of clinical studies? If so, were the search strategy and rules for inclusion or exclusion outlined? 3.3. Were observational data or assumptions used to establish effectiveness? If so, what are the potential biases in results?

Q4. Were all the important and relevant costs and consequences for each alternative identified?

4.1. Was the range wide enough for the research question at hand? 4.2. Did it cover all relevant viewpoints? (Possible viewpoints include the community or social viewpoint, and those of patients and third-party payers. Other viewpoints may also be relevant depending upon the particular analysis.) 4.3. Were the capital costs, as well as operating costs, included?

Q5. Were costs and consequences measured accurately in appropriate physical units (for example, hours of nursing time, number of physician visits, lost work-days, gained life-years)?

5.1. Were the sources of resource utilization described and justified? 5.2. Were any of the identified items omitted from measurement? If so, does this mean that they carried no weight in the subsequent analysis? 5.3. Were there any special circumstances (e.g., joint use of resources) that made measurement difficult? Were these circumstances handled appropriately?

Q6. Were costs and consequences valued credibly?

6.1. Were the sources of all values clearly identified? (Possible sources include market values, patient or client preferences and views, policy-makers’ views, and health professionals’ judgements) 6.2. Were market values employed for changes involving resources gained or depleted? 6.3. Where market values were absent (e.g. volunteer labour), or market values did not reflect actual values (such as clinic space donated at a reduced rate), were adjustments made to approximate market values? 6.4. Was the valuation of consequences appropriate for the question posed (i.e. has the appropriate type or types of analysis – cost-effectiveness, cost-benefit, cost-utility – been selected)?

Q7. Were costs and consequences adjusted for differential timing?

7.1. Were costs and consequences that occur in the future ‘discounted’ to their present values? 7.2. Was any justification given for the discount rate used?

Q8. Was an incremental analysis of costs and consequences of alternatives

8.1. Were the additional (incremental) costs generated by one alternative over another compared to the additional effects, benefits, or utilities generated?


*Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL. Methods for the economic evaluation of health care programmes. 3nd ed. Oxford.Oxford University Press. 2005. Included types of full economic evaluations†

Cost-effectiveness analysis:

“The cost-effectiveness analysis is an economic study in which the costs are expressed in monetary units and the results in non-monetary units. Non-monetary units may for example be: (1) years of life gained, (2) hospital days prevented, (3) clinical parameters (e.g. response or remission rates, reduction in cholesterol,etc)”.

Cost-utility analysis:

performed? Q9. Was allowance made for uncertainty in the estimates of costs and consequences?

9.1. If patient-level data on costs or consequences were available, were appropriate statistical analyses performed? 9.2. If a sensitivity analysis was employed, was justification provided for the ranges or distributions of values (for key study parameters), and the form of sensitivity analysis used? 9.3. Were the conclusions of the study sensitive to the uncertainty in the results, as quantified by the statistical and/or sensitivity analysis?

Q10. Did the presentation and discussion of study results include all issues of concern to users?

10.1. Were the conclusions of the analysis based on some overall index or ratio of costs to consequences (for example, cost-effectiveness ratio)? If so, was the index interpreted intelligently or in a mechanistic fashion? 10.2. Were the results compared with those of others who have investigated the same question? If so, were allowances made for potential differences in study methodology? 10.3. Did the study discuss the generalizability of the results to other settings and patient/client groups? 10.4. Did the study allude to, or take account of, other important factors in the choice or decision under consideration (for example, distribution of costs and consequences, or relevant ethical issues)? 10.5. Did the study discuss issues of implementation, such as the feasibility of adopting the ‘preferred’ programme given existing financial or other constraints, and whether any freed resources could be redeployed to other worthwhile programmes?


“The cost-utility analysis follows the same principle as the cost-effectiveness analysis. Costs are assessed in monetary units and the benefit is measured as a non-monetary but utility-adjusted outcome, the quality adjusted life year (QALY). The concept combines life expectancy and quality of life. If quality of life is animportant aspect of therapy, this form of analysis should be chosen”.

†Walter E. et al. (April 2006). Guidelines on Health Economic Evaluation: Consensus paper. Institute for Pharmaeconomic Research; Vienna.

Perspective** of the economic evaluation

Patients

“The term patient refers to the person targeted by the health intervention under consideration (certain programs might refer to patients as clients).

The perspective of the patient is appropriate, for example, in a comparison of treating a disease on an outpatient versus an inpatient basis.

The difference in costs between the outpatient and inpatient options (e.g., work absenteeism, disturbance in family life, and length of recovery) might influence a patient's preference for one option or the other”.

Providers

“The term provider refers to all categories of persons and institutions providing health-related services.

Examples of providers include physicians, hospitals, nursing homes, public health clinics, and local and state health departments. The provider perspective can be that of:

• a conglomerate of providers (i.e., a managed-care organization [MCO]), or • a provider within that conglomerate (i.e., one hospital or physician).

The provider perspective is appropriate, for example, when assessing the costs and benefits of establishing and operating a childhood immunization reminder system. From the clinic's perspective, direct medical costs would be included, but productivity losses associated with a patient's going to the clinic to receive the immunization would not be included”.

Payers


“The term payer refers to the person, entity, or institution ultimately responsible for the financial cost of a program, intervention, or medical procedure.

In the United States, payers include

• households that pay for care out-of-pocket or through insurance premiums, • businesses that pay for part of the cost of health insurance, • private insurers (e.g., MCOs), • public insurance programs (e.g., Medicare and Medicaid), and • federal or state governments.

An analysis of the impact of a law mandating health plans to cover the cost of fertility drug treatment is an example of an economic evaluation that could be implemented from the payer perspective — in this case, the private health insurer”.

Health Care System

“The health-care system perspective is broader than the perspective of the health-care provider. The health-care system perspective considers the costs and outcomes associated with providing care without differentiating between categories of providers or payers.

The health-care system perspective is useful and informative if the economic burden of a disease is frequently shared by all categories of payers and providers.

For example, the costs and outcomes of STDs are the responsibilities of

• public health clinics, • public health laboratories, • primary-care practitioners, • obstetricians, • gynecologists, • family planning clinics, and • hospitals.

The use of a health-care system perspective can provide a more complete estimate of the true medical costs and outcomes of treating STDs than can an estimate from a single category of payers or providers”.

Society

“The societal perspective is the broadest possible perspective, because it includes all costs (no matter who incurs them) and all consequences (both good and bad), regardless of who experiences them.

For example, when estimating the cost of acquired immunodeficiency (AIDS) from a societal perspective, the analyst should consider not only diagnosis and treatment costs but also


• productivity losses associated with the premature death of AIDS patients, • the financial and emotional costs incurred by families and friends caring for AIDS patients, and • the cost to families and society of caring for orphaned children of AIDS patients.

The government perspective is used in studies that are being conducted for the public sector, but the government perspective should not be confused with the societal perspective, which is broader because it encompasses all costs and consequences.

For example, costs incurred by the patient seeking care would not be included in a study conducted from a governmental or public budget perspective, but would be considered relevant from a societal perspective”.

**From CDC website:Framing an EconomicEvaluation. Available at: http://www.cdc.gov/owcd/eet/framing3/fixed/1.html

http://www.cdc.gov/owcd/eet/framing3/fixed/1.html�


Appendix 8: List of included studies

1 Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, Masson EA, McCollum PT. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. European Journal of Vascular & Endovascular Surgery 2003, 25 (6): 513-518.

2 Adderley U, Smith R. Topical agents and dressings for fungating wounds. Cochrane Database of Systematic Reviews 2007, 2: 3948.

3 Akagi I, Furukawa K, Miyashita M, Kiyama T, Matsuda A, Nomura T, Makino H, Hagiwara N, Takahashi K, Uchida E. Surgical wound management made easier and more cost-effective. Oncology Letters 2012, 4 (1): 97-100.

4 Baba-Akbari Sari A, Flemming K, Cullum NA, Wollina U. Therapeutic ultrasound for pressure ulcers. Cochrane Database Syst Rev. 2006 Jul 19 (3):CD001275.

5 Albert NM, Rock R, Sammon MA, Bena JF, Morrison SL, Whitman A, Kato I, Landis-Erdman JC. Do patient and nurse outcome differences exist between 2 negative pressure wound therapy systems? Journal of Wound, Ostomy, & Continence Nursing 2012, 39 (3): 259-266.

6 Amsler F, Willenberg T, Blattler W. In search of optimal compression therapy for venous leg ulcers: a meta-analysis of studies comparing diverse corrected bandages with specifically designed stockings. Journal of Vascular Surgery 2009, 50 (3): 668- 674.

7 Apelqvist J, Armstrong DG, Lavery LA, Boulton AJ. Resource utilization and economic costs of care based on a randomized trial of vacuum-assisted closure therapy in the treatment of diabetic foot wounds. American Journal of Surgery 2008, 195 (6): 782-788.

8 Apelqvist J, Ragnarson- Tennvall G. Cavity foot ulcers in diabetic patients: a comparative study of cadexomer iodine ointment and standard treatment. An economic analysis alongside a clinical trial. Acta Dermato-Venereologica 1996, 76 (3): 231-235.

9 Apelqvist J, Ragnarson-Tennvall G, Persson U, Larsson J. Diabetic foot ulcers in a multidisciplinary setting. An economic analysis of primary healing and healing with amputation. Journal of internal medicine 1994, 235 (5): 463-471.

10 Augustin M, Siegel A, Heuser A, Vanscheidt W. Chronic leg ulcers: Cost evaluation of two treatment strategies. Journal of Dermatological Treatment 1999, 10 (Suppl. 1): S21-S25.

11 Aziz Z, Cullum NA, Flemming K. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database Syst Rev. 2011, Mar 16 (3): CD002933.

12 Bale S, Hagelstein S, Banks V, Harding KG. Costs of dressings in the community. Journal of wound care 1998, 7 (7): 327-330.

13 Barber C, Watt A, Pham C, Humphreys K, Penington A, Mutimer K, Edwards M, Maddern G. Influence of bioengineered skin substitutes on diabetic foot ulcer and venous leg ulcer outcomes (Structured abstract). Journal Wound Care 2008, 17 (12): 517-527.

14 Bardy J, Slevin NJ, Mais KL, Molassiotis AA. Systematic review of honey uses and its potential value within oncology care (Structured abstract). Journal of Clinical Nursing 2008, 17 (3): 2604-2623.

15 Bergin SM, Wraight P. Silver based wound dressings and topical agents for treating diabetic foot ulcers. Cochrane Database Systematic Reviews 2006, Jan 25 (1): CD005082.

http://www.ncbi.nlm.nih.gov/pubmed?term=Baba-Akbari%20Sari%20A%5BAuthor%5D&cauthor=true&cauthor_uid=16855964�

http://www.ncbi.nlm.nih.gov/pubmed?term=Flemming%20K%5BAuthor%5D&cauthor=true&cauthor_uid=16855964�

http://www.ncbi.nlm.nih.gov/pubmed?term=Cullum%20NA%5BAuthor%5D&cauthor=true&cauthor_uid=16855964�

http://www.ncbi.nlm.nih.gov/pubmed?term=Wollina%20U%5BAuthor%5D&cauthor=true&cauthor_uid=16855964�

http://www.ncbi.nlm.nih.gov/pubmed/16855964�

http://www.ncbi.nlm.nih.gov/pubmed?term=Aziz%20Z%5BAuthor%5D&cauthor=true&cauthor_uid=21412880�

http://www.ncbi.nlm.nih.gov/pubmed?term=Cullum%20NA%5BAuthor%5D&cauthor=true&cauthor_uid=21412880�

http://www.ncbi.nlm.nih.gov/pubmed?term=Flemming%20K%5BAuthor%5D&cauthor=true&cauthor_uid=21412880�


http://www.ncbi.nlm.nih.gov/pubmed?term=Influence%20of%20bioengineered%20skin%20substitutes%20on%20diabetic%20foot%20ulcer%20and%20venous%20leg%20ulcer%20outcomes�

http://www.ncbi.nlm.nih.gov/pubmed?term=.%20Silver%20based%20wound%20dressings%20and%20topical%20agents%20for%20treating%20diabetic%20foot%20ulcers�


16 Berliner E, Ozbilgin B, Zarin DA. A systematic review of pneumatic compression for treatment of chronic venous insufficiency and venous ulcers. Journal of Vascular Surgery 2003, 37 (3): 539-544.

17 Blozik E, Scherer M. Skin replacement therapies for diabetic foot ulcers: systematic review and meta-analysis (Structured abstract). Diabetes Care 2008, 31(4): 693-4.

18 Boogaard M, Laat E, Spauwen P, Schoonhoven L. The effectiveness of topical negative pressure in the treatment of pressure ulcers: a literature review (Structured abstract). European Journal of Plastic Surgery 2008, 31 (1): 1-7.

19 Bosanquet N, Franks P, Moffatt C, Connolly M, Oldroyd M, Brown P, Greenhalgh R, McCollum C. Community leg ulcer clinics: cost-effectiveness. Health trends 1993, 25 (4): 146-148.

20 Bouza C, Munoz A, Amate JM. Efficacy of modern dressings in the treatment of leg ulcers: a systematic review (Structured abstract). Wound Repair Regen. 2005, May-Jun 13(3): 218-29.

21 Bouza C, Saz Z, Munoz A, Amate JM. Efficacy of advanced dressings in the treatment of pressure ulcers: a systematic review (Structured abstract). J Wound Care 2005, 14 (5): 193-199.

22 Braakenburg A, Obdeijn MC, Feitz R, Van Rooij IA, Van Griethuysen AJ, Klinkenbijl JH. The clinical efficacy and cost effectiveness of the vacuum-assisted closure technique in the management of acute and chronic wounds: a randomized controlled trial. Plastic & Reconstructive Surgery 2006, 118 (2): 390-397.

23 Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D. Systematic reviews of wound care management: (2). Dressings and topical agents used in the healing of chronic wounds. Health technology assessment 1999, 3(17 Pt 2): 1-35.

24 Bradley M, Cullum N, Sheldon T. The debridement of chronic wounds: A systematic review. Health technology assessment 1999, 3(17): 73.

25 Branom R, Rappl LM. Constant force technology versus low-air-loss therapy in the treatment of pressure ulcers. Ostomy Wound Management 2001, 47(9): 38-46.

26 Burgos A, Gimenez J, Moreno E, Lamberto E, Utrera M, Urraca EM, Velez FJ, Lopez E, Martinez MA, Gomez MJ, Garcia L. Cost, efficacy, efficiency and tolerability of collagenase ointment versus hydrocolloid occlusive dressing in the treatment of pressure ulcers. A comparative, randomised, multicentre study. Clinical Drug Investigation 2000, 19(5): 357-365.

27 Cannavo M, Fairbrother G, Owen D, Ingle J, Lumley T. A comparison of dressings in the management of surgical abdominal wounds. Journal of wound care 1998, 7(2): 57-62.

28 Capasso VA, Munro BH. The cost and efficacy of two wound treatments. AORN Journal 2003, 77(5): 984-992.

29 Carls GS, Gibson TB, Driver VR, Wrobel JS, Garoufalis MG, Defrancis RR, Wang S, Bagalman JE, Christina JR. The economic value of specialized lower-extremity medical care by podiatric physicians in the treatment of diabetic foot ulcers. Journal of the American Podiatric Medical Association 2011, 101(2): 93-115.

30 Carter MJ, Tingley-Kelley K, Warriner RA. Silver treatments and silver-impregnated dressings for the healing of leg wounds and ulcers: a systematic review and meta-analysis (Structured abstract). Journal of the American Academy of Dermatology 2010, 63(4): 668-679.

http://www.ncbi.nlm.nih.gov/pubmed?term=Skin%20replacement%20therapies%20for%20diabetic%20foot%20ulcers%3A%20systematic%20review%20and%20meta-analysis�

http://www.ingentaconnect.com/content/klu/238;jsessionid=6cjfnblb8htrf.victoria�



31 Chambers H, Dumville JC, Cullum N. Silver treatments for leg ulcers: a systematic review. Wound Repair & Regeneration 2007, 15(2): 165-173.

32 Chang KW, Alsagoff S, Ong KT, Sim PH. Pressure ulcers-randomised controlled trial comparing hydrocolloid and saline gauze dressings. Medical Journal of Malaysia 1998, 53(4): 428-431.

33 Chen M, Zheng H, Yin LP, Xie CG. Is oral administration of Chinese herbal medicine effective and safe as an adjunctive therapy for managing diabetic foot ulcers? A systematic review and meta-analysis. (Provisional abstract). J Altern Complement Med. 2010, 16(8): 889-898

34 Cherry GW, Ryan TJ. Using cycloidal vibration to heal venous leg ulcers: a cost-analysis based on retrospective data. Journal of wound care 2005, 14(4): 177-178.

35 Chuangsuwanich A, Charnsanti O, Lohsiriwat V, Kangwanpoom C, Thong-In N. The efficacy of silver mesh dressing compared with silver sulfadiazine cream for the treatment of pressure ulcers. Journal of the Medical Association of Thailand 2011, 94(5): 559-565.

36 Chuck AW, Hailey D, Jacobs P, Perry DC. Cost-effectiveness and budget impact of adjunctive hyperbaric oxygen therapy for diabetic foot ulcers. International Journal of Technology Assessment in Health Care 2008, 24(2): 178-183.

37 Clay PG, Graham MR, Lindsey CC, Lamp KC, Freeman C, Glaros A. Clinical efficacy, tolerability, and cost savings associated with the use of open-label metronidazole plus ceftriaxone once daily compared with ticarcillin/clavulanate every 6 hours as empiric treatment for diabetic lower-extremity infections in older males. American Journal of Geriatric Pharmacotherapy 2004, 2(3): 181-189.

38 Clegg JP, Guest JF. Modelling the cost-utility of bio-electric stimulation therapy compared to standard care in the treatment of elderly patients with chronic non-healing wounds in the UK. Current Medical Research & Opinion 2007, 23(4): 871-883.

39 Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta- analysis of adjunctive therapy with micronized purified flavonoid fraction. European Journal of Vascular & Endovascular Surgery 2005, 30(2): 198-208.

40 Colwell JC, Foreman MD, Trotter J P. A comparison of the efficacy and cost-effectiveness of two methods of managing pressure ulcers. Decubitus 1993, 6(4): 28-36.

41 Cruciani M, Lipsky BA, Mengoli C, Lalla F. Are granulocyte colony-stimulating factors beneficial in treating diabetic foot infections: a meta-analysis (Structured abstract). Diabetes Care 2005, 28(2): 454-460.

42 Cruciani M, Lipsky BA, Mengoli C, de Lalla Fausto. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database Syst Rev. 2009, Jul 8(3): CD006810.

43 Cullum N, Deeks J, Sheldon TA, Song F, Fletcher AW. Beds, mattresses and cushions for pressure sore prevention and treatment. Cochrane Database Syst Rev. 2000, 2: CD001735.

44 Cullum N, Nelson EA, Flemming F, Sheldon T. Systematic reviews of wound care management: (5) beds, (6) compression, (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy (Brief record). Health Technol Assess. 2001, 5(9):1-221.

45 Cullum N, Petherick E. Pressure ulcers. Clin Evid (Online) 2008, Mar 19: pii 1901. 46 Cullum N, Al-Kurdi D, Bell-Syer SM. Therapeutic ultrasound for venous leg ulcers.

Cochrane Database Syst Rev. 2010, Jun 16(6): CD001180.


http://www.ncbi.nlm.nih.gov/pubmed?term=Are%20granulocyte%20colony-stimulating%20factors%20beneficial%20in%20treating%20diabetic%20foot%20infections%3A%20a%20meta-analysis�

http://www.ncbi.nlm.nih.gov/pubmed?term=Systematic%20reviews%20of%20wound%20care%20management%3A%20(5)%20beds%2C%20(6)%20compression%2C%20(7)%20laser%20therapy%2C%20therapeutic%20ultrasound%2C%20electrotherapy%20and%20electromagnetic%20therapy�




47 Damiani G, Pinnarelli L, Sommella L, Tocco MP, Marvulli M, Magrini P, Ricciardi W. Vacuum-assisted closure therapy for patients with infected sternal wounds: a meta-analysis of current evidence (Provisional abstract). J Plast Reconstr Aesthet Surg 2011, Sep 64(9):1119-23.

48 Dat AD, Poon F, Pham KB, Doust J. Aloe vera for treating acute and chronic wounds. Cochrane Database of Systematic Reviews 2012, Feb 15(2): CD008762.

49 DePalma RG, Kowallek D, Spence RK, Caprini JA, Nehler MR, Jensen J, Goldman MP, Bundens WP. Comparison of costs and healing rates of two forms of compression in treating venous ulcers. Vascular surgery 1999, 33(6): 683-690.

50 Dumville JC, Deshpande S, O'Meara S, Speak K. Foam dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2011, Sep 7(9): CD009111.

51 Dumville JC, Deshpande S, O'Meara S, Speak K. Hydrocolloid dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2012, Feb 15(2): CD009099.

52 Dumville JC, Deshpande S, O'Meara S, Speak K. Alginate dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2012, Feb 15(2): CD009110.

53 Dumville JC, O'Meara S, Deshpande S, Speak K. Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2011, Sep 7(9): CD009101.

54 Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, Iglesias C, McCaughan D, Mitchell JL, Nelson EA, Torgerson DJ, VenUS II team. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers. Health technology assessment 2009, 13(55): 1-182.

55 ECRI. Air-fluidized beds used for treatment of pressure ulcers in the home environment (Structured abstract). Agency for Healthcare Research and Quality 2001, 3(72): 72.

56 Edmonds M, Gough A, Solovera J, Standaert B. Filgrastim in the treatment of infected diabetic foot ulcers. Retrospective cost analysis of a phase II randomised clinical trial. Clinical Drug Investigation 1999, 17(4): 275-286.

57 Edwards J, Stapley S. Debridement of diabetic foot ulcers. Cochrane Database Syst Rev. 2010, Jan 20(1): CD003556.

58 Evans D, Land L. Topical negative pressure for treating chronic wounds: A systemic review. British journal of plastic surgery 2001, 54(3): 238-242.

59 Falagas ME, Matthaiou DK, Vardakas KZ. Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials (Structured abstract). Mayo Clin Proc. 2006, 81(12): 1553-66.

60 Fernandez R, Griffiths R. Water for wound cleansing. Cochrane Database Syst Rev. 2012, Feb 15(2): CD003861.

61 Ferrell BA, Keeler E, Siu AL, Ahn SH, Osterweil D. Cost-effectiveness of low-air-loss beds for treatment of pressure ulcers. Journals of Gerontology Series A-Biological Sciences & Medical Sciences 1995, 50(3): M141-6.

62 Fitzgerald O'Connor EJ, Vesely M, Holt PJ, Jones KG, Thompson MM, Hinchliffe RJ. A systematic review of free tissue transfer in the management of non-traumatic lower extremity wounds in patients with diabetes. European Journal of Vascular & Endovascular Surgery 2011, 41(3): 391-399.

63 Flemming K, Cullum NA. Laser therapy for venous leg ulcers. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001182.

http://www.ncbi.nlm.nih.gov/pubmed?term=Dumville%20JC%5BAuthor%5D&cauthor=true&cauthor_uid=21901731�

http://www.ncbi.nlm.nih.gov/pubmed?term=Deshpande%20S%5BAuthor%5D&cauthor=true&cauthor_uid=21901731�

http://www.ncbi.nlm.nih.gov/pubmed?term=O'Meara%20S%5BAuthor%5D&cauthor=true&cauthor_uid=21901731�

http://www.ncbi.nlm.nih.gov/pubmed?term=Speak%20K%5BAuthor%5D&cauthor=true&cauthor_uid=21901731�
















http://www.ncbi.nlm.nih.gov/pubmed?term=Fluoroquinolones%20vs%20beta-lactams%20for%20empirical%20treatment%20of%20immunocompetent%20patients%20with%20skin%20and%20soft%20tissue%20infections%3A%20a%20meta-analysis%20of%20randomized%20controlled%20trials�



64 Fletcher A, Cullum N, Sheldon TA. A systematic review of compression treatment for venous leg ulcers (Brief record). BMJ 1997, 315(7108): 576-80.

65 Foglia E, Restelli U, Napoletano AM, Coclite D, Porazzi E, Bonfanti M, Croce D. Pressure ulcers management: an economic evaluation. Journal of Preventive Medicine & Hygiene 2012, 53(1): 30-36.

66 Fujimoto Y, Shimooka N, Ohnishi Y, Yoshimine T. Clinical evaluation of hydrocolloid dressings for neurosurgical wounds. Surgical neurology 2008, 70(2): 217-220.

67 Gibbons GW, Marcaccio EJ, Jr Burgess AM, Pomposelli FB, Jr Freeman DV, Campbell DR, Miller A, LoGerfo FW. Improved quality of diabetic foot care, 1984 vs 1990. Reduced length of stay and costs, insufficient reimbursement. Archives of Surgery 1993, 128(5): 576-581.

68 Glinski W, Chodynicka B, Roszkiewicz J, Bogdanowski T, Lecewicz-Torun B, Kaszuba A, Bowszyc J, Nowak A, Wnorowski J, Wasik F, Glinska-Ferenz M, Blaszczyk M, Strzyga P, Pachocki R. The beneficial augmentative effect of micronised purified flavonoid fraction (MPFF) on the healing of leg ulcers: An open, multicentre, controlled, randomised study. Phlebology 1999, 14(4): 151-157.

69 Gordon L, Edwards H, Courtney M, Finlayson K, Shuter P, Lindsay E. A cost-effectiveness analysis of two community models of care for patients with venous leg ulcers. Journal of wound care 2006, 15(8): 348-353.

70 Granick MS, Posnett J, Jacoby M, Noruthun S, Ganchi PA, Datiashvili RO.Efficacy and cost-effectiveness of a high-powered parallel water jet for wound debridement. Wound Repair & Regeneration 2006, 14(4): 394-397.

71 Graumlich JF, Blough LS, McLaughlin RG, Milbrandt JC, Calderon CL, Agha SA, Scheibel LW. Healing pressure ulcers with collagen or hydrocolloid: a randomized, controlled trial. Journal of the American Geriatrics Society 2003, 51(2): 147-154.

72 Greer DM, Morris J, Walsh NE, Glenn AM, Keppler J. Cost-effectiveness and efficacy of air-fluidized therapy in the treatment of pressure ulcers. Journal of enterostomal therapy 1988, 15(6): 247-251.

73 Guest JF, Taylor RR, Vowden K, Vowden P. Relative cost-effectiveness of a skin protectant in managing venous leg ulcers in the UK. Journal of wound care 2012, 21(8): 389-394.

74 Guo S, Counte MA, Gillespie KN, Schmitz H. Cost-effectiveness of adjunctive hyperbaric oxygen in the treatment of diabetic ulcers. International Journal of Technology Assessment in Health Care 2003, 19(4): 731-737.

75 Habacher W, Rakovac I, Gorzer E, Haas W, Gfrerer RJ, Wach P, Pieber TR. A model to analyse costs and benefit of intensified diabetic foot care in Austria. Journal of evaluation in clinical practice 2007, 13(6): 906-912.

76 Hansson C. The effects of cadexomer iodine paste in the treatment of venous leg ulcers compared with hydrocolloid dressing and paraffin gauze dressing. Cadexomer Iodine Study Group. International journal of dermatology 1998, 37(5): 390-396.

77 Harris C, Shannon R. An innovative enterostomal therapy nurse model of community wound care delivery: a retrospective cost-effectiveness analysis. Journal of Wound, Ostomy, & Continence Nursing 2008, 35(2): 169-183.

78 Heyneman A, Beele H, Vanderwee K, Defloor T. A systematic review of the use of hydrocolloids in the treatment of pressure ulcers (Structured abstract). J Clin Nurs. 2008, 17(9): 1164-73.




79 Hinchliffe RJ, Andros G, Apelqvist J, Bakker K, Fiedrichs S, Lammer J, Lepantalo M, Mills JL, Reekers J, Shearman CP, Valk G, Zierler RE, Schaper NC. A systematic review of the effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral arterial disease (Provisional abstract). Diabetes Metab Res Rev. 2012, 28(Suppl 1): 179-217.

80 Hinchliffe RJ, Valk GD, Apelqvist J, Armstrong DG, Bakker K, Game FL, Hartemann-Heurtier A, Londahl M, Price PE, van Houtum WH, Jeffcoate WJ. A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes/Metabolism Research Reviews 2008, 24(Suppl 1): S119-44.

81 Hiskett G. Clinical and economic consequences of discharge from hospital with on-going TNP therapy: a pilot study. Journal of tissue viability 2010, 19(1): 16-21.

82 Ho C, Tran K, Hux M, Sibbald G, Campbell K. Artificial skin grafts in chronic wound care: a meta-analysis of clinical efficacy and a review of cost-effectiveness (Provisional abstract). [Technology report no 52]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2005.

83 Horswell RL, Birke JA, Patout CA Jr. A staged management diabetes foot program versus standard care: a 1-year cost and utilization comparison in a state public hospital system. Archives of Physical Medicine & Rehabilitation 2003, 84(12): 1743-1746.

84 Hu X, Sun H, Han C, Wang X, Yu W. Topically applied rhGM-CSF for the wound healing: a systematic review. Burns 2011, 37(5): 729-741.

85 Hunt DL. Diabetes: foot ulcers and amputations. Clin Evid (Online). 2011 Aug 26: pii: 0602.

86 Hurd T, Zuiliani N, Posnett J. Evaluation of the impact of restructuring wound management practices in a community care provider in Niagara, Canada. International Wound Journal 2008, 5(2): 296-304.

87 Iglesias CP, Claxton K. Comprehensive decision-analytic model and Bayesian value-of-information analysis: pentoxifylline in the treatment of chronic venous leg ulcers. PharmacoEconomics 2006, 24(5): 465-478.

88 Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, VenUS Team. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers. Health technology assessment 2004, 8(29): iii, 1-105.

89 Jansen JP, Kumar R, Carmeli Y. Accounting for the development of antibacterial resistance in the cost effectiveness of ertapenem versus piperacillintazobactam in the treatment of diabetic foot infections in the UK. PharmacoEconomics 2009, 27(12): 1045-1056.

90 Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, Amery CM, Edmonds ME, Gibby OM, Johnson AB, Jones GR, Masson E, Patmore JE, Price D, Rayman G, Harding KG. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes. Health technology assessment 2009, 13(54): 1-86.

91 Johannsen F, Gam AN, Karlsmark T. Ultrasound therapy in chronic leg ulceration: a meta-analysis. Wound Repair & Regeneration 1998, 6(2): 121-126.

92 Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2007, 18(2):CD001737.

93 Jull AB, Rodgers A, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2008, 8(4): CD005083.

http://www.ncbi.nlm.nih.gov/pubmed?term=A%20systematic%20review%20of%20the%20effectiveness%20of%20revascularization%20of%20%20the%20ulcerated%20foot%20in%20patients%20with%20diabetes%20and%20peripheral%20arterial%20disease�

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http://www.ncbi.nlm.nih.gov/pubmed?term=Birke%20JA%5BAuthor%5D&cauthor=true&cauthor_uid=14669177�

http://www.ncbi.nlm.nih.gov/pubmed?term=Patout%20CA%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=14669177�

http://www.ncbi.nlm.nih.gov/pubmed?term=Hu%20X%5BAuthor%5D&cauthor=true&cauthor_uid=20926197�

http://www.ncbi.nlm.nih.gov/pubmed?term=Sun%20H%5BAuthor%5D&cauthor=true&cauthor_uid=20926197�

http://www.ncbi.nlm.nih.gov/pubmed?term=Han%20C%5BAuthor%5D&cauthor=true&cauthor_uid=20926197�

http://www.ncbi.nlm.nih.gov/pubmed?term=Wang%20X%5BAuthor%5D&cauthor=true&cauthor_uid=20926197�

http://www.ncbi.nlm.nih.gov/pubmed?term=Yu%20W%5BAuthor%5D&cauthor=true&cauthor_uid=20926197�



http://www.ncbi.nlm.nih.gov/pubmed?term=Jull%20AB%5BAuthor%5D&cauthor=true&cauthor_uid=18843679�

http://www.ncbi.nlm.nih.gov/pubmed?term=Rodgers%20A%5BAuthor%5D&cauthor=true&cauthor_uid=18843679�

http://www.ncbi.nlm.nih.gov/pubmed?term=Walker%20N%5BAuthor%5D&cauthor=true&cauthor_uid=18843679�





94 Jull A, Walker N, Parag V, Molan P, Rodgers A; Honey as Adjuvant Leg Ulcer Therapy trial collaborators. Randomized clinical trial of honey-impregnated dressings for venous leg ulcers. British Journal of Surgery 2008, 95(2): 175-182.

95 Jull A, Waters J, Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review (Brief record). Lancet 2002, 359(9317): 1550-4.

96 Junger M, Arnold A, Zuder D, Stahl HW, Heising S. Local therapy and treatment costs of chronic, venous leg ulcers with electrical stimulation (Dermapulse): a prospective, placebo controlled, double blind trial. Wound Repair & Regeneration 2008, 16(4): 480-487.

97 Kerstein MD. Unexpected economics of ulcer care protocols. Southern medical journal 2004, 97(2): 135-136.

98 Kerstein MD, Gahtan V. Outcomes of venous ulcer care: results of a longitudinal study. Ostomy Wound Management 2000, 46(6): 22-26.

99 Kerstein MD, Gemmen E, Van Rijswijk L, Lyder CH, Phillips T, Xakellis G, Golden K, Harrington C. Cost and cost effectiveness of venous and pressure ulcer protocols of care. Disease Management and Health Outcomes 2001, 9(11): 651-663.

100 Kikta MJ, Schuler JJ, Meyer JP, Durham JR, Eldrup-Jorgensen J, Schwarcz TH, Flanigan DP. A prospective, randomized trial of Unna's boots versus hydroactive dressing in the treatment of venous stasis ulcers. Journal of Vascular Surgery 1988, 7(3): 478-483.

101 Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2012, 4: CD004123.

102 Lafferty B, Wood L, Davis P. Improved care and reduced costs with advanced wound dressings. Wounds UK 2011, 7(1): 14-23.

103 Langer G, Schloemer G, Knerr A, Kuss O, Behrens J. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database of Systematic Reviews 2003, 4: 3216.

104 Lavery LA, Boulton AJ, Niezgoda JA, Sheehan P. A comparison of diabetic foot ulcer outcomes using negative pressure wound therapy versus historical standard of care. International Wound Journal 2007, 4(2): 103-113.

105 Levy E, Levy P. Venous leg ulcer: A costly disease for French society. Results from a prospective medicoeconomic observational study. Phlebolymphology 2001, 35(11): 15.

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system-wide assessment of wound care interventions: a ......committee members and wound care content...

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